PGC-1α regulation by exercise training and its
influences on muscle function and insulin sensitivity
Vitor A. Lira, Carley R. Benton, Zhen Yan and Arend Bonen
Am J Physiol Endocrinol Metab 299:E145-E161, 2010. First published 6 April 2010;
doi:10.1152/ajpendo.00755.2009
You might find this additional info useful...
This article cites 229 articles, 158 of which can be accessed free at:
http://ajpendo.physiology.org/content/299/2/E145.full.html#ref-list-1
This article has been cited by 5 other HighWire hosted articles
Regulation of exercise-induced fiber type transformation, mitochondrial biogenesis, and
angiogenesis in skeletal muscle
Zhen Yan, Mitsuharu Okutsu, Yasir N. Akhtar and Vitor A. Lira
J Appl Physiol, January, 2011; 110 (1): 264-274.
[Abstract] [Full Text] [PDF]
Potential therapeutic role of resistance training in diabetes: a contribution by the 2009
recipient of the APS New Investigator Award
Charles H. Lang
Am J Physiol Endocrinol Metab, January, 2011; 300 (1): E1-E2.
[Full Text] [PDF]
Increased fatigue resistance linked to Ca2+-stimulated mitochondrial biogenesis in muscle
fibres of cold-acclimated mice
Joseph D. Bruton, Jan Aydin, Takashi Yamada, Irina G. Shabalina, Niklas Ivarsson, Shi-Jin
Zhang, Masanobu Wada, Pasi Tavi, Jan Nedergaard, Abram Katz and Håkan Westerblad
J Physiol, November, 1 2010; 588 (21): 4275-4288.
[Abstract] [Full Text] [PDF]
Nitric oxide and AMPK cooperatively regulate PGC-1α in skeletal muscle cells
Vitor A. Lira, Dana L. Brown, Ana K. Lira, Andreas N. Kavazis, Quinlyn A. Soltow, Elizabeth
H. Zeanah and David S. Criswell
J Physiol, September, 15 2010; 588 (18): 3551-3566.
[Abstract] [Full Text] [PDF]
Updated information and services including high resolution figures, can be found at:
http://ajpendo.physiology.org/content/299/2/E145.full.html
Additional material and information about AJP - Endocrinology and Metabolism can be found at:
http://www.the-aps.org/publications/ajpendo
This infomation is current as of February 26, 2011.
AJP - Endocrinology and Metabolism publishes results of original studies about endocrine and metabolic systems on any level of
organization. It is published 12 times a year (monthly) by the American Physiological Society, 9650 Rockville Pike, Bethesda MD
20814-3991. Copyright © 2010 by the American Physiological Society. ISSN: 0193-1849, ESSN: 1522-1555. Visit our website at
http://www.the-aps.org/.
Downloaded from ajpendo.physiology.org on February 26, 2011
Metabolic benefits of resistance training and fast glycolytic skeletal muscle
Nathan K. LeBrasseur, Kenneth Walsh and Zoltan Arany
Am J Physiol Endocrinol Metab, January, 2011; 300 (1): E3-E10.
[Abstract] [Full Text] [PDF]
Am J Physiol Endocrinol Metab 299: E145–E161, 2010.
First published April 6, 2010; doi:10.1152/ajpendo.00755.2009.
Review
PGC-1␣ regulation by exercise training and its influences on muscle function
and insulin sensitivity
Vitor A. Lira,1 Carley R. Benton,2 Zhen Yan,1* and Arend Bonen2*
1
Center for Skeletal Muscle Research, Robert M. Berne Cardiovascular Research Center, University of Virginia School
of Medicine, Charlottesville, Virginia; and 2Department of Human Health and Nutritional Sciences, University of Guelph,
Guelph, Ontario, Canada
Submitted 18 December 2009; accepted in final form 30 March 2010
Downloaded from ajpendo.physiology.org on February 26, 2011
Lira VA, Benton CR, Yan Z, Bonen A. PGC-1␣ regulation by exercise training
and its influences on muscle function and insulin sensitivity. Am J Physiol
Endocrinol Metab 299: E145–E161, 2010. First published April 6, 2010;
doi:10.1152/ajpendo.00755.2009.—The peroxisome proliferator-activated receptor-␥ (PPAR␥) coactivator-1␣ (PGC-1␣) is a major regulator of exercise-induced
phenotypic adaptation and substrate utilization. We provide an overview of 1) the
role of PGC-1␣ in exercise-mediated muscle adaptation and 2) the possible
insulin-sensitizing role of PGC-1␣. To these ends, the following questions are
addressed. 1) How is PGC-1␣ regulated, 2) what adaptations are indeed dependent
on PGC-1␣ action, 3) is PGC-1␣ altered in insulin resistance, and 4) are PGC-1␣knockout and -transgenic mice suitable models for examining therapeutic potential
of this coactivator? In skeletal muscle, an orchestrated signaling network, including
Ca2⫹-dependent pathways, reactive oxygen species (ROS), nitric oxide (NO),
AMP-dependent protein kinase (AMPK), and p38 MAPK, is involved in the control
of contractile protein expression, angiogenesis, mitochondrial biogenesis, and other
adaptations. However, the p38␥ MAPK/PGC-1␣ regulatory axis has been confirmed to be required for exercise-induced angiogenesis and mitochondrial biogenesis but not for fiber type transformation. With respect to a potential insulinsensitizing role of PGC-1␣, human studies on type 2 diabetes suggest that PGC-1␣
and its target genes are only modestly downregulated (ⱕ34%). However, studies in
PGC-1␣-knockout or PGC-1␣-transgenic mice have provided unexpected anomalies, which appear to suggest that PGC-1␣ does not have an insulin-sensitizing role.
In contrast, a modest (⬃25%) upregulation of PGC-1␣, within physiological limits,
does improve mitochondrial biogenesis, fatty acid oxidation, and insulin sensitivity
in healthy and insulin-resistant skeletal muscle. Taken altogether, there is substantial evidence that the p38␥ MAPK-PGC-1␣ regulatory axis is critical for exerciseinduced metabolic adaptations in skeletal muscle, and strategies that upregulate
PGC-1␣, within physiological limits, have revealed its insulin-sensitizing effects.
endurance exercise; angiogenesis; mitochondria; fatty acid metabolism; glucose
to changes in contractile
activity and to changes in the substrate/endocrine milieu.
Although the molecular bases for these adaptive responses had
remained uncertain for many years, the peroxisome proliferator-activated receptor-␥ (PPAR␥) coactivator 1␣ (PGC-1␣) has
revealed itself to be a major regulator of exercise-induced
phenotypic adaptation and substrate utilization. In the present
paper, we provide an overview and perspective on the mechanisms by which PGC-1␣ is regulated by endurance exercise
training as well as on the influence of PGC-1␣ on fiber type
transformation, angiogenesis, mitochondrial biogenesis, lipid
metabolism, and insulin sensitivity.
The first part of this review examines 1) the pathways
involved in PGC-1␣ regulation in response to endurance exSKELETAL MUSCLE IS HIGHLY ADAPTABLE
* These authors contributed equally to this article.
Address for reprint requests and other correspondence: A. Bonen, Dept. of
Human Health and Nutritional Sciences, Univ. of Guelph, Guelph, ON, N1G
2W1, Canada (e-mail: abonen@uoguelph.ca).
http://www.ajpendo.org
ercise or increased contractile activity and 2) the role of
PGC-1␣ in endurance exercise-induced adaptations in skeletal
muscle. The second half of this review examines whether
PGC-1␣ acts as an insulin-sensitizing agent, since one of the
most beneficial and clinically relevant effects of exercise is the
improvement in insulin sensitivity in skeletal muscle. To this
end, the impact of type 2 diabetes on PGC-1␣ expression and
function as well as the use of in vivo models to examine the
role of this coactivator as a therapeutic target are discussed.
PGC-1␣ Function in Skeletal Muscle
PGC-1␣, a transcriptional coactivator identified through its
interaction with PPAR␥ in brown fat cells, was found to be
greatly upregulated in brown fat and skeletal muscle in response to cold exposure (159). PGC-1␣ is now known to be
involved in the regulation of thermogenesis, energy metabolism, and other biological processes that are critical in controlling phenotypic characteristics of various organ systems (112,
158, 159, 213). PGC-1␣ interacts with and coactivates a
0193-1849/10 Copyright © 2010 the American Physiological Society
E145
Review
E146
PGC-1␣, EXERCISE TRAINING, AND INSULIN SENSITIVITY
AJP-Endocrinol Metab • VOL
PGC-1␣ Regulation in Response to Exercise
Multiple signaling pathways act to regulate PGC-1␣ in
skeletal muscle. Table 1 summarizes the main findings of
studies investigating pathways potentially involved in PGC-1␣
regulation in vivo. These and other reports are discussed in the
following paragraphs. Current evidence supports that p38␥
MAPK signaling is functionally required for endurance exercise-induced PGC-1␣ regulation. This signaling-transcription
regulatory axis may present a node of cross-talk with other
signaling pathways reviewed here.
Ca2⫹/calmodulin-dependent signaling. Rhythmic skeletal
muscle contractions activate the Ca2⫹/calmodulin-dependent
serine/threonine protein phosphatase calcineurin (CnA) and
Ca2⫹/calmodulin-dependent protein kinases (CaMKs). CnA
has been implicated in the expression of slow-twitch muscle
genes through dephosphorylation and activation of the nuclear
factor of activated T cells (NFAT) (37, 183). Transgenic mice
overexpressing constitutively active CnA in skeletal muscle
present an increased number of slow-twitch myofibers and
elevated expression of slow-twitch troponin I, myoglobin,
GLUT4, pyruvate dehydrogenase kinase-4 (PDK4), mitochondrial enzymes, and PGC-1␣ (142, 174). These mice have low
levels of carbohydrate oxidation rates along with high lipid
oxidation rates in the glycolytic extensor digitorum longus
(EDL) muscle (123, 174) and present enhanced endurance
exercise performance (97). The phenotypic changes observed
are similar to the ones reported in muscle-specific PGC-1␣transgenic mice (28, 116, 215) and consistent with the notion
that CnA activates MEF2 and induces PGC-1␣ transcription
(72, 227). Genetic and pharmacological interventions that inhibit or abolish CnA/NFAT activity have consistently reduced
slow-twitch muscle gene expression (129) and blocked mechanical overload-induced transformation of fibers to type IIa
and type I (134). However, animals treated with cyclosporine
A, a pharmacological inhibitor of CnA, presented normal
upregulation of PGC-1␣ and mitochondrial enzymes in response to endurance exercise training (57). Therefore, there is
strong evidence for an essential functional role of the CnANFAT regulatory axis in the maintenance of slow-twitch myofibers and in the promotion of IIb/IId/x-to-IIa fiber type transformation in response to increased contractile activity. A direct
role of this signaling pathway in the upregulation of PGC-1␣
and metabolic adaptations in skeletal muscle, especially in the
context of exercise, is not currently supported.
CaMKs have been shown to act synergistically with CnA to
activate slow and oxidative fiber-specific gene expression in
cultured myocytes (226). Skeletal muscle expression of CaMKIV
has also been suggested to link energy deprivation to increased
expression of PGC-1␣ and mitochondrial biogenesis in skeletal
muscle (230). The forced expression of a constitutively active
CaMKIV in skeletal muscle in transgenic mice increases expression of the PGC-1␣ gene and enhances mitochondrial biogenesis
along with reduced fatigability of EDL muscle (225). However,
genetic disruption of the CaMKIV gene did not prevent exerciseinduced upregulation of PGC-1␣ and IIb-to-IIa fiber type transformation (4). Actually, current evidence does not support the
expression of CaMKIV in skeletal muscle (171). However, it is
possible that a different CaMK, such as CaMKII or CaMKK or
other protein kinases, may act upon substrates targeted by the
299 • AUGUST 2010 •
www.ajpendo.org
Downloaded from ajpendo.physiology.org on February 26, 2011
growing list of transcription factors and nuclear receptors,
including estrogen-related receptor-␣ (88, 89, 159), thyroid
receptor (159), nuclear respiratory factor-1 (NRF-1) (227),
NRF-2 (136), and myocyte enhancer factor 2 (MEF2) (72,
132). As a consequence, PGC-1␣ is involved in the coordinated regulation of nuclear- and mitochondrial-encoded genes
required for contractile and metabolic adaptations in skeletal
muscle (158, 177, 215). Importantly, PGC-1␣ expression per
se is also regulated by PGC-1␣ via its interaction with MEF2
on its own promoter in a feed-forward regulatory loop (72).
PGC-1␣ activity is regulated by posttranslational modifications
through phosphorylation (93), sumoylation (175), and deacetylation (29). Therefore, posttranslational activation of PGC-1␣
will lead to enhanced expression of target genes as well as
PGC-1␣ itself.
Skeletal muscle is essential for locomotive and other daily
activities, and under insulin-stimulated conditions this tissue
removes 70 –90% of a glucose load (48, 49, 102). In mammals,
skeletal muscles present a mosaic of different fiber types.
Based on the expression of the predominant isoform of myosin
heavy-chain proteins, myofibers can be classified as type I, IIa,
IId/x, and IIb (54, 201). Type I fibers are slow-twitch fibers
(slow contractile force development) (219) and have an oxidative profile (high mitochondrial content and capillary density)
(156, 187). These myofibers also actively express glucose
transporter 4 (GLUT4) (60) and present great sensitivity to
insulin (79). Type IIa fibers are fast-twitch fibers (fast contractile force development) (53) but have similar oxidative profiles
to the type I fibers, whereas type IId/x fibers are fast-twitch
fibers with a glycolytic metabolic profile (low mitochondrial
content and capillary density) (156), express low GLUT4 (60),
and have low sensitivity to insulin stimulation (79). Rodents
also have type IIb fibers with an even more fast-twitch, glycolytic phenotype than type IId/x fibers (166, 167). It is
important to note that insulin sensitivity can be affected within
a given fiber type by several mechanisms. These will be
discussed in more detail in subsequent sections.
It is well known that increased contractile activity, such as
endurance exercise training, promotes phenotypic adaptations in
skeletal muscle toward a more oxidative phenotype. Specifically,
endurance exercise training leads to fiber type transformation,
mitochondrial biogenesis, angiogenesis, and other adaptive changes
in skeletal muscles along with improved insulin sensitivity and
metabolic flexibility in both rodents and humans (38, 43, 65, 82,
105, 179, 184, 203). The orchestrated regulation of these processes is of extreme elegance, and current findings suggest that
PGC-1␣ is a key player for several of these adaptations.
Animal and cellular genetic models with altered expression
of the PGC-1␣ gene have provided much of the evidence for
the role of PGC-1␣ in fiber type specificity (116), mitochondrial biogenesis (70), angiogenesis (5), GLUT4 expression (72,
132), and improved exercise performance (28). In addition,
PGC-1␣ mRNA and protein expressions are very responsive to
endurance exercise (11, 67, 90, 153, 172, 199). In the face of
the growing body of knowledge underscoring the importance of
PGC-1␣ in skeletal muscle phenotype determination, the two
critical questions to be addressed in the context of exercise are
1) how PGC-1␣ is regulated and 2) what adaptations are indeed
dependent on PGC-1␣ action.
AJP-Endocrinol Metab • VOL
299 • AUGUST 2010 •
www.ajpendo.org
Dominant-negative
AMPK␣2
Global AMPK␣2
and global
AMPK␣1-KO*13
Reactive oxygen
species
Pharmacological
inhibition of
xanthine oxidase
(allopurinol)
AMPK
Pharmacological
activation
(AICAR,
metformin)
Mutated
AMPK␥3*11
(genetic
activation)
eNOS and
nNOS-KO*8
Reactive nitrogen
species
Pharmacological
inhibition of NOS
(L-NAME)*8
CaMKIV-KO
CaMKIV
Constitutively active
CaMKIV
Reduced induction (protein) [⬃88
min of treadmill running]
Not tested
Not tested
Not tested
Normal induction (mRNA) [90min run test]
*mRNA and protein
*mRNA
NmRNA*12
NmRNA
Normal induction (mRNA) [1 and
9 days, 60 min of treadmill
running]
Higher induction (mRNA) [⬃53
min of treadmill running]
Normal induction (mRNA and
protein) [nerve stimulation and 4
wk of training]
Not tested
Normal induction (mRNA and
protein) [5-days of exercise]
Not tested
Not tested
NmRNA eNOS-KO,
*mRNA
nNOS-KO
NProtein
NProtein
*mRNA
Not tested
*Protein
Calcineurin
Constitutively active
calcineurin
*Cytochrome c, *GLUT4, *activity
of citrate synthase, malate
dehydrogenase, hexokinase II, and
␤-HAD, *exercise performance
*NRF-1, *NRF-2, *TFAM,
*cytochrome c, *COX IV and
*citrate synthase mRNAs,
*mitochndrial area and protein
expression of respiratory complexes
NCytochrome c protein, NALAS
mRNA
NFOXO1, Nhexokinase II, NPDK4
mRNA (both ␣1-KO and ␣2-KO),
NGLUT4, NCPT1, NUCP3
mRNA (␣2-KO)
Not tested
NCOX-III and NCOX IV mRNA,
NCOX activity, NCOX IV protein,
Ncitrate synthase and ␤-HAD
activities
*NRF-1, *NRF-2, *TFAM mRNA
(all in nNOS-KO), no changes in
eNOS-KO
*Mitochondrial DNA, *slow-twitch
fibers, *myoglobin protein, *CPT I
protein
*Type I fibers, +exercise performance
*Slow-twitch fibers, *troponin I,
*myoglobin, *GLUT4, *PDK4,
*mitochondrial enzymes, *lipid
oxidation rates, +CHO oxidation
rates, *exercise performance
+COX I protein, +COX IV protein
Basal*5
29*9, 93*10,
141, 195,
218
58
230
98
Not tested
Not tested
Not tested
*FOXO1, *hexokinase II, *PDK4
mRNA (both ␣1-KO and ␣2-KO)
Continued
101
210
211
4
225
57
97, 123, 142,
174
References
+NRF-1, +TFAM protein (compared with
exercise untreated)
*NRF2␣ mRNA, *cytochrome c protein
(both eNOS and nNOS-KO)
*TFAM mRNA in EDL (compared with
sedentary L-NAME-treated controls)
*myoglobin, *MHCIIa and *COXIV
proteins, +exercise performance
Not tested
*ERR␣, *PPAR␦, *NRF-2, *TFAM
mRNA and several mitochondrial
proteins (except COX I and COX IV;
compared with sedentary vehicle-treated
controls)
Not tested
In Response to Exercise*6
Skeletal Muscle Phenotype*4
PGC-1␣, EXERCISE TRAINING, AND INSULIN SENSITIVITY
Downloaded from ajpendo.physiology.org on February 26, 2011
Pharmacological
inhibition
(cyclosporine A)
Basal PGC-1␣ Level*2
Signaling Pathway/Model
Exercise-Induced PGC-1␣
Upregulation*3
Table 1. Evidence for basal and exercise-induced PGC-1␣ regulation in adult skeletal muscle of rodents in vivo*1
Review
E147
299 • AUGUST 2010 •
www.ajpendo.org
NCytochrome c, NCOX IV,
Ncapillary density
*Type IIb to IIa/IIx fiber type shift,
Ncytochrome c and COX IV (to 4 wk
of running), NVEGF (nerve
stimulation)
References
154
3
168
168
PGC-1␣, peroxisome proliferator-activated receptor (PPAR)␥ coactivator-1␣; GLUT4, glucose transporter 4; PDK4, pyruvate dehydrogenase kinase-4; CHO, carbohydrate; COX I, III, and IV, cytochrome
oxidase I, III, and IV; ALAS, ␣-aminolevulinate synthase; ERR␣, estrogen-related receptor-␣; NRF-1 and -2, nuclear respiratory factor-1 and -2; TFAM, mitochondrial transcription factor A; CPT I, carnitine
palmitoyl transferase I; MHCIIa, myosin heavy chain IIa; EDL, extensor digitorum longus; L-NAME, NG-nitro-L-arginine methyl ester; FOXO1, forkhead box-containing protein O1; NOS, nitric oxide
synthase; eNOS and nNOS, endothelial and neuronal isoforms of NOS, respectively; KO, knockout; AICAR, 5-aminoimidazole-4-carboxamide-1-␤-D-ribofuranoside; ␤-HAD, ␤-hydroxyacyl-CoA
dehydrogenase; AMPK, AMP-activated protein kinase; MKK6, mitogen-activated protein kinase kinase-6. +Reduction; Nno change; *increase; *1Refer to text and original references for details. *2,*5Results
for basal levels of PGC-1␣ and skeletal muscle phenotype under basal conditions are in comparison with untreated wild-type mice or wild-type littermates. *3Results for exercise-induced PGC-1␣ upregulation
are in comparison with exercised wild-type mice (pharmacological treatments) or exercised wild-type littermates (genetic manipulations) submitted to the specified exercise protocol in square brackets. *4Only
the main findings are listed. *6Results for skeletal muscle phenotype in response to exercise are in comparison with the same genotype when sedentary and/or not nerve stimulated (unless when specified in
brackets). *7Findings suggest that COX I and COX IV mRNA upregulation was normal, but some sort of toxicity imposed by cyclosporine A prevented these proteins from being upregulated. *8Only results
for the EDL muscle are presented. *9Cantó et al. (29) demonstrated that PGC-1␣ is activated by sirtuin 1-mediated deacetylation following PGC-1␣ phosphorylation by AMPK (via AICAR stimulation).
*10Jäger et al. (93) demonstrated that AMPK (via AICAR stimulation) directly phosphorylates and activates PGC-1␣. *11Trangenic mice expressing the mutant AMPK␥3 R225Q that increases the activity
of the AMPK complex, preferentially expressed in glycolytic muscle. *12At basal levels, PGC-1␣ expression was not affected, but PGC-1␣ upregulation in response to ␤-guanidinopropionic acid (a creatine
analog) was prevented. *13Only results for the quadriceps muscle are presented.
Reduced induction (mRNA) [nerve
stimulation]
Not tested
Downloaded from ajpendo.physiology.org on February 26, 2011
AJP-Endocrinol Metab • VOL
NmRNA
*COX IV
Not tested
*Protein
*Citrate synthase activity, *succinate
dehydrogenase activity, *%type IIa/IIx
fibers, Nhexokinase II protein
NCitrate synthase activity, Nsuccinate
dehydrogenase activity, N%type IIa/IIx
fibers, Nhexokinase II protein
In Response to Exercise*6
Skeletal Muscle Phenotype*4
Normal induction (protein) [6 wk
of voluntary wheel running]
Basal*5
*Protein
Mutated AMPK␥1
(muscle-specific
activation)
p38 MAPK
MKK6 musclespecific
overexpression
(upstream kinase
of p38 MAPKs)
p38␥ MAPK
muscle-specific
KO
Normal induction (protein) [6 wk
of voluntary wheel running]
Exercise-Induced PGC-1␣
Upregulation*3
+Citrate synthase activity, +%type
IIa/IIx fibers, Nhexokinase II
protein
*Citrate synthase activity, *% type
IIa/IIx fibers, *hexokinase II protein
+Protein
Basal PGC-1␣
Level*2
E148
AMPK␣2 musclespecific KO
Signaling Pathway/Model
Table 1.—Continued
Review
PGC-1␣, EXERCISE TRAINING, AND INSULIN SENSITIVITY
Review
PGC-1␣, EXERCISE TRAINING, AND INSULIN SENSITIVITY
AJP-Endocrinol Metab • VOL
between NO and O2⫺, is also found in the extracellular fluid of
muscle during contraction (149). Most studies point toward
H2O2 as an important signaling molecule for metabolic adaptations in skeletal muscle. Silveira et al. (186) showed that
H2O2 produced by contracting skeletal muscle cells was required for PGC-1␣ upregulation. Irrcher et al. (91) observed
that treatment of skeletal muscle cells with H2O2 reduced
cellular ATP levels, activated AMPK, and increased PGC-1␣
mRNA, suggesting that H2O2 can promote PGC-1␣ expression
through AMPK. Interestingly, increased H2O2 production has
been proposed as an indirect mechanism by which lactate, a
by-product of glycolysis, upregulates PGC-1␣ (75). Most importantly, ROS has been shown to be functionally important
for endurance exercise-induced PGC-1␣ expression and metabolic adaptation in skeletal muscle. High-dose antioxidant
supplementation blocks endurance exercise-induced upregulation of transcriptional regulators, including PGC-1␣ and genes
involved in mitochondrial biogenesis (63, 165), and precludes
the beneficial effect of endurance exercise on insulin sensitivity
in humans (165). More recently, it has been reported that
pharmacological inhibition of xanthine oxidase with allopurinol suppresses the exercise-induced upregulation in PGC-1␣ in
parallel to blunted activation (i.e., phosphorylation) of p38
MAPK in rats. These findings suggest that ROS is involved in
p38 MAPK activation and subsequent regulation of PGC-1␣
expression in response to contraction in vivo (101). Future
studies should focus on the precise molecular mechanism by
which ROS influences exercise-induced PGC-1␣ regulation
and muscle adaptation.
AMPK signaling. AMPK, a sensor of metabolic stress and
energy deprivation, is also activated by contractile activity in
skeletal muscle (55, 69, 74, 217, 218, 220). Multiple mechanisms for AMPK-mediated PGC-1␣ regulation have been postulated. First, exercise-induced AMPK activation is associated
with HDAC5 phosphorylation, nuclear export, and derepression of PGC-1␣ transcription in human skeletal muscle (130,
209). Second, AMPK has been shown to stimulate the cAMP
response element-binding protein (202), the upstream stimulatory factor, and possibly GATA4 in transcriptional activation
of the PGC-1␣ gene in cultured cells (72, 92). Third, both
phosphorylation and deacetylation of PGC-1␣ are required for
upregulation of the PGC-1␣ gene and mitochondrial genes (29,
93). Mechanistically, AMPK directly activates PGC-1␣ by
phosphorylating Thr177 and Ser538 (93), which is required for
PGC-1␣ deacetylation by HDAC sirtuin 1 (SIRT1) (29). Interestingly, AMPK activates SIRT1 indirectly by stimulating
␤-oxidation and subsequently increasing the NAD⫹/NADH
ratio (29) and by promoting the expression of nicotinamide
phosphoribosyltransferase in NAD⫹ biogenesis (45, 56). Endurance exercise in humans can also stimulate SIRT1 through
this latter mechanism (45, 56), and a single bout of exercise
induces PGC-1␣ deacetylation especially in the glycolytic
EDL and gastrocnemius muscles, correlating with upregulation
of PGC-1␣ target genes such as PDK4, GLUT4, and carnitine
palmitoyl transferase Ib (29).
Pharmacological activation of AMPK by 5-aminoimidazole-4carboxamide-1-␤-D-ribofuranoside (AICAR) increases PGC-1␣
gene expression and mitochondrial biogenesis in skeletal muscle
(195, 218). In addition, AICAR enhances the running ability of
mice even in the absence of exercise training (141). Mice expressing a gain-of-function mutation in the regulatory ␥3-subunit of
299 • AUGUST 2010 •
www.ajpendo.org
Downloaded from ajpendo.physiology.org on February 26, 2011
constitutively active form of CaMKIV and mediate skeletal muscle plasticity.
CaMKII, the main CaMK isoform in skeletal muscle (36,
170, 171), is activated (phosphorylated) by endurance exercise
(160, 170, 171). Caffeine treatment of adult skeletal muscle
ex vivo at levels that increase cytosolic calcium but are
insufficient to cause contraction activated CaMKII (224) along
with p38 MAPK activation, PGC-1␣ upregulation, and mitochondrial biogenesis (222). These adaptations appeared to be
dependent on both CaMKII and p38 MAPK activities because
the CaMKII inhibitor KN93 blocked p38 MAPK activation,
and the p38 MAPK inhibitor SB-202190 prevented mitochondrial biogenesis (222). These ex vivo studies provide insights
into Ca2⫹-dependent signaling in skeletal muscle by circumventing other cellular events that occur during contraction.
However, CaMKII requirement for exercise-induced upregulation of PGC-1␣ and adaptation remains to be determined.
More recently, endurance exercise in humans has been shown
to lead to nuclear export of class IIa histone deacetylase
(HDAC)4 and HDAC5 along with activation of CaMKII and
AMP-activated protein kinase (AMPK) in skeletal muscle
(130). HDAC5 normally inhibits MEF2 activity and represses
PGC-1␣ transcription in skeletal muscle (46, 72). These observations suggest a potential pathway for CaMKII regulation
of PGC-1␣ during exercise. Finally, CaMKK has been shown
to be a kinase of AMPK (96, 221) responsible for AMPK
activation during contractions in skeletal muscle (96). Therefore, CaMKII and CaMKK may function as upstream kinases
in exercise-induced regulation of PGC-1␣ via regulation of p38
MAPK, HDAC5, and AMPK activation. However, these hypotheses would benefit from experiments with loss-of-function
approaches in animal models of exercise in vivo.
Reactive nitrogen and oxygen species-dependent signaling.
Nitric oxide (NO) production is increased during contractile activity (13, 149, 185). Both endothelial and neuronal isoforms of
NO synthase (eNOS and nNOS, respectively) have been shown to
be activated by Ca2⫹/calmodulin and AMPK (34, 35, 47, 161,
197). Several studies suggest a role of endogenous NO in AMPKand Ca2⫹-dependent regulation of PGC-1␣, GLUT4, and mitochondrial genes (119, 128). NO is also required for functional
overload-induced upregulation of slow myosin heavy chain
(MHC; type 1/␤) (182) through modulation of Akt and glycogen
synthase kinase-3␤ (GSK-3␤) activities and amplification of
CnA/NFAT-dependent signaling (51). In support of this,
eNOS⫺/⫺ muscle cells have reduced type 1 MHC expression (52),
and low levels of NO donors promote mitochondrial biogenesis,
PGC-1␣, and GLUT4 expression in cultured muscle cells (119,
145) through a mechanism involving AMPK␣1 activation (Lira
VA and Criswell DS, unpublished data). However, neither pharmacological inhibition (by NG-nitro-L-arginine methyl ester) in
rats nor genetic deletion of eNOS or nNOS genes in mice prevents
endurance exercise-induced PGC-1␣ mRNA expression in skeletal muscle (210, 211). Altogether, these studies support a role for
NO in PGC-1␣ regulation, mitochondrial biogenesis, and fast-toslow fiber type transformation but not in the exercise-induced
increase in PGC-1␣.
There is also ample evidence for increased reactive oxygen
species (ROS) in the form of superoxide anions (O2⫺), hydrogen peroxide (H2O2), and hydroxyl radical (OH⫺) in skeletal
muscle during contraction (41, 101, 126, 127, 149, 162, 186).
Peroxynitrite (ONOO⫺), an oxidant formed by a reaction
E149
Review
E150
PGC-1␣, EXERCISE TRAINING, AND INSULIN SENSITIVITY
AJP-Endocrinol Metab • VOL
transformation in these mice. Of note, a parallel study employing muscle-specific genetic disruption of the PGC-1␣ gene (61)
showed that these mice had the same phenotype as the p38␥
MAPK muscle-specific KO mice with impaired metabolic
adaptations but normal contractile adaptation to exercise (see
below for details). These findings provide functional confirmation for the p38␥ MAPK-PGC-1␣ regulatory axis in exerciseinduced skeletal muscle adaptation (Fig. 1) and genetically
separate the metabolic adaptation from contractile adaptation
in a physiological model of exercise in mice.
PGC-1␣ and Exercise-Induced Adaptations
Animal and cellular genetic models provide much of the
evidence for a functional role of PGC-1␣ in fiber type specification (72, 116), GLUT4 (132), PDK4 (215), and mitochondrial protein expression (72, 109, 111) as well as angiogenesis
(5) in skeletal muscle. However, few studies have examined
whether PGC-1␣ is indeed required for exercise-induced adaptations and what aspects of the adaptive responses, if not all,
are affected by the absence of functional PGC-1␣ in skeletal
muscle.
Leick et al. (110) employed a mouse model of global gene
disruption of the PGC-1␣ gene (PGC-1␣-KO) and showed that
PGC-1␣-KO mice had increases in hexokinase II, aminolevulinate synthase 1, and cytochrome oxidase (COX) I protein
expression in response to endurance exercise despite the fact
that these mice had reduced basal level expression of these
metabolic enzymes. They concluded that PGC-1␣ is not mandatory for exercise- and training-induced adaptive gene responses. Adhihetty et al. (1) extended these findings, confirming that PGC-1␣-KO mice have normal voluntary running
activity and reduced basal level mitochondrial respiratory function, which can be corrected by endurance exercise training.
However, other reports document that PGC-1␣-KO mice suffer
from hyperactivity due to lesions in the central nervous system,
and that these animals have circadian rhythm abnormalities,
and present AMPK activation in resting skeletal muscle (70,
117, 121). Therefore, an approach with skeletal muscle-spe-
Fig. 1. Signaling pathways involved in exercise-induced peroxisome-proliferator-activated receptor-␥ coactivator-1␣ (PGC-1␣) regulation in skeletal
muscle. Current evidence suggests roles for calcineurin (CnA), CaMK, AMPactivated protein kinase (AMPK), and p38 MAPK in PGC-1␣ regulation.
Thick arrows depict regulatory events required for exercise-mediated induction
of PGC-1␣ and subsequent adaptations that have been confirmed by gene
deletion studies in animal models. Thin arrows depict regulatory events that
have been associated with PGC-1␣ regulation, but their requirement for the
exercise-dependent induction of PGC-1␣ awaits further investigation (refer to
text for details). ROS, reactive oxygen species.
299 • AUGUST 2010 •
www.ajpendo.org
Downloaded from ajpendo.physiology.org on February 26, 2011
AMPK, expressed predominantly in glycolytic fibers, present
increased expression of PGC-1␣ and other transcription factors
associated with mitochondrial biogenesis (58). More recently,
Cantó et al. (30) have demonstrated that exercise-induced
PGC-1␣ deacetylation was blunted in AMPK␥3-knockout (KO)
mice. On the other hand, animals expressing a dominant-negative
form of AMPK (dnAMPK␣2) in skeletal muscle present normal
PGC-1␣ mRNA levels but are unable to upregulate PGC-1␣,
mitochondrial DNA, and enzyme activity in response to ␤-guanidinopropionic acid, a creatine analog that causes metabolic
stress (230). These findings are consistent with the notion that
AMPK serves as a metabolic sensor that regulates PGC-1␣ expression and promotes mitochondrial biogenesis in skeletal muscle.
However, a muscle-specific expression of a dominant-negative
form of AMPK blunted IIb-to-IIa/IIx fiber type transformation in
response to voluntary running without affecting the induction of
PGC-1␣ expression or mitochondrial enzyme activity (168). Furthermore, genetic deletion of functional AMPK isoforms failed to
block exercise-induced PGC-1␣ gene expression in skeletal muscle (98). Therefore, it remains to be fully determined whether
endurance exercise-induced skeletal muscle adaptation depends
on functional AMPK.
p38 MAPK signaling. Various types of exercise lead to
activation of the stress-activated protein kinases, including
c-Jun-NH2-terminal kinases, p38 MAPKs, and ERKs in skeletal muscle of humans and rodents (9, 10, 66, 216). Of those,
early evidence pointed toward p38 MAPK as the one most
likely involved in PGC-1␣ regulation. p38 MAPK phosphorylates and activates PGC-1␣ (157) as well as MEF2 (228) and
activating transcription factor 2 (ATF2) (31), which are transcription factors that bind to the PGC-1␣ promoter. In this
context, Akimoto et al. (3) demonstrated that p38 MAPK acts
through ATF2 phosphorylation to induce PGC-1␣ expression
in skeletal muscle and that muscle-specific overexpression of
the upstream kinase (mitogen-activated protein kinase kinase-6) of p38 MAPK resulted in upregulation of PGC-1␣ and
mitochondrial proteins in glycolytic muscles. In a subsequent
study, Akimoto et al. (2) observed that PGC-1␣ transcriptional
control in response to motor nerve stimulation required functional interaction of ATF2 with the PGC-1␣ promoter. These
studies provided initial genetic evidence for the role of p38
MAPK in exercise-induced skeletal muscle metabolic phenotype.
Wright et al. (223) observed that p38 MAPK and ATF2
phosphorylation occur in parallel with PGC-1␣ translocation to
the nucleus shortly after an exhaustive bout of swimming
exercise. These events coincided with increases in citrate
synthase and cytochrome c mRNAs and preceded the upregulation in PGC-1␣ protein. These observations allude to another
potential mechanism of p38 MAPK-mediated activation of
PGC-1␣, which seems to occur prior to increased PGC-1␣
transcription. The signals responsible for PGC-1␣ activation
and translocation to the nucleus remain to be determined, but it
is likely that phosphorylation and/or deacetylation of PGC-1␣
is required for this process.
More recently, Pogozelski et al. (154) demonstrated that
p38␥ MAPK, but not p38␣ MAPK or p38␤ MAPK, is required
for PGC-1␣ upregulation in mitochondrial biogenesis and
angiogenesis in response to voluntary wheel running and nerve
stimulation in mice. None of the p38 MAPK isoforms was
required for endurance exercise-induced IIb-to-IIa fiber type
Review
PGC-1␣, EXERCISE TRAINING, AND INSULIN SENSITIVITY
cific gene disruption was then desirable to minimize potential
confounding factors of the global PGC-1␣-KO models.
Recently, muscle-specific PGC-1␣-KO (PGC-1␣-MKO) mice
were generated (70, 71), and these animals presented reduced
locomotive activity, maximal exercise tolerance, and impaired
muscle function, consistent with reduced oxidative capacity in
skeletal muscles. Despite the fact that PGC-1␣-MKO mice exhibited normal voluntary running activity and normal IIb-to-IIa
fiber type transformation in skeletal muscles that are recruited
during exercise, endurance exercise-induced expression of mitochondrial enzymes (cytochrome c and COX IV) and increases in
platelet endothelial cell adhesion molecule-1-positive endothelial
cells were significantly attenuated (61). These findings from
PGC-1␣-MKO underscore the importance of PGC-1␣ in mitochondrial biogenesis and angiogenesis, but not fiber type transformation, in response to endurance exercise training.
For more than two decades, a number of studies have
demonstrated the benefits of exercise and muscle contraction
on improving insulin sensitivity in rodents and in humans (24,
50, 77, 78, 143, 163, 181, 205, 212, 229). More recently, a key
prospective study has shown conclusively that a modest program of moderate exercise (“brisk walking”, 150 min/wk)
along with a modest weight loss (⫺7%, or ⫺5.6 kg) over ⬃3
yr markedly reduced the incidence of type 2 diabetes (104).
With the discovery of PGC-1␣ (227) and its exercise-mimetic
effects on muscle metabolism (cf. Ref. 73) and the subsequent
discovery of PGC-1␤ (114), a PGC-1␣ homolog, considerable
interest arose as to whether these coactivators had a role in
skeletal muscle insulin sensitivity (73, 113).
PGC-1␣ and PGC-1␤ share a similar tissue distribution and
are expressed in tissues characterized with a high mitochondrial content, including skeletal muscle (108, 114, 131). There
seems to be considerable redundancy of function between
PGC-1␣ and PGC-1␤. For example, PGC-1␤, like PGC-1␣,
activates genes involved with fatty acid oxidation and mitochondrial biogenesis (7, 100, 114, 115, 131, 176, 190), and in
muscle cells PGC-1␣ and -␤ increased the mRNAs of GLUT4
(132, 139). However, in lean and insulin-resistant (obese) human
muscle, PGC-1␣ and -␤ protein expression were not correlated,
and only PGC-1␣ protein correlated with rates of palmitate
oxidation and citrate synthase activity, an index of mitochondrial
content (85). With exercise training only PGC-1␣ mRNA was
increased (105, 131, 140), whereas PGC-1␤ mRNA was not
altered (105, 131) or was reduced (140). With respect to changes
in skeletal muscle with aging (118) and type 2 diabetes (148),
some have observed reductions in both PGC-1␣ and -␤ mRNA
(118, 148), whereas others have observed only a reduction in
skeletal muscle PGC-1␤ mRNA in senescence-prone animals
(169) and reductions in PGC-1␣ mRNA, but not PGC-1␤ mRNA,
in type 2 diabetes (204). Collectively, these observations begin to
suggest that although PGC-1␤ and PGC-1␣ may share similar
functions, they also appear to have some different roles. However,
only skeletal muscle PGC-1␣ expression is consistently downregulated in type 2 diabetes. Indeed, work in cell lines has shown
that PGC-1␣ induces exercise-mimetic effects, increasing mitochondrial biogenesis, fatty acid oxidation, GLUT4 expression,
and insulin signaling (132), leading to speculations (73, 105, 113)
AJP-Endocrinol Metab • VOL
that the molecular basis for the exercise-mediated improvement in
glucose transport is attributable, in part, to PGC-1␣.
Lipids, Glucose Transport, and PGC-1␣
There is a strong association between skeletal muscle insulin
resistance and circulating plasma fatty acid concentrations
(18 –20) and intramuscular triacylglycerol accumulation (94,
95, 107, 147, 192). However, in athletes intramuscular triacylglycerol depots are also increased, yet they are insulin
sensitive (208), possibly as a result of an enhanced capacity for
fatty acid oxidation (22, 25, 64, 87). This anomaly between
increased intramuscular triacylglycerol depots and improved
insulin sensitivity was termed the “athlete paradox.” However,
recent work indicates that this is much less of a paradox than was
once thought. It is the more soluble, bioactive lipid metabolites
such as ceramide, diacylglycerol, and long-chain fatty acyl-CoAs,
not intramuscular triacylglycerol storage depots (22, 81, 120), that
impair postreceptor insulin signaling, thereby interfering with
GLUT4 translocation and glucose transport (32, 33, 80, 193, 194).
The increase in intramuscular triacylglycerol depots, whether in
athletes or in insulin-resistant muscles, appears to be an attempt to
limit intramuscular muscle lipotoxicity, since intracellular triacylglycerol provides a cytoprotective role in lipid-overload states
(120, 122).
In insulin resistance and type 2 diabetes, intramuscular lipid
accumulation does not result from a reduced intrinsic capacity
for fatty acid oxidation by mitochondria (83, 84, 86, 135, 207),
as had been widely believed (103, 152). Instead, intramuscular
lipids accumulation stems, in part, from a FAT/CD36-mediated
increase in fatty acid uptake (23, 62, 83, 124). The excess fatty
acids taken up cannot be oxidized away (23, 83, 106), because
there is an insufficient compensatory increase in mitochondrial
mass (68, 83) or an insufficient capacity for fatty acid oxidation
(106), or alternatively, the mitochondrial mass may be reduced
(86, 138, 152). These observations may be the reason that an
improvement in fatty acid oxidation (e.g., with exercise),
which allows excess fatty acids to be oxidized away, has so
often been associated with improved insulin sensitivity (26, 87,
150). Indeed, exercise training improves fatty acid oxidation
not only during exercise (151, 191, 196) but also at rest (65,
188), since under basal conditions there are training-induced
increases in mitochondrial carnitine palmitoyl transferase I
activity, resulting in an increased rate of fatty acid oxidation by
isolated mitochondria under basal conditions (27). A comparable effect could well be provoked by PGC-1␣ since, similarly
to exercise training, PGC-1␣ induces mitochondrial biogenesis
and fatty acid oxidation (cf. Ref. 73 and 113), thereby integrating the upregulation in fatty acid oxidation with improvements in insulin sensitivity.
Whether fatty acids regulate PGC-1␣ expression in muscle
has been controversial. Palmitate (0.75 mM), but not oleate,
reduced PGC-1␣ mRNA by 66% in C2C12 muscle cells and
appeared to involve MAPK-ERK 1/2 and nuclear factor-␬␤
activation (44). Similarly, in humans, prolonged (48 h) lipid
infusion increased circulating fatty acids 3.6-fold (0.48 –1.73
mM) and reduced muscle PGC-1␣ mRNA by 30% (164). In
contrast, prolonged fasting for 24 or 48 h, which increased
circulating fatty acids 1.6- and 2.1-fold, respectively, did not
alter muscle PGC-1␣ mRNA or protein (206). Contradictory
results have also been observed when circulating fatty acids
299 • AUGUST 2010 •
www.ajpendo.org
Downloaded from ajpendo.physiology.org on February 26, 2011
Exercise, Insulin Sensitivity, and PGC-1
E151
Review
E152
PGC-1␣, EXERCISE TRAINING, AND INSULIN SENSITIVITY
were reduced by acipimox (12) or nicotinic acid (214), since
these treatments reduced (12) or increased PGC-1␣ mRNA
(214), respectively. Taken altogether, it is difficult to conclude
that fatty acids influence the expression of PGC-1␣.
Type 2 Diabetes and PGC-1␣
AJP-Endocrinol Metab • VOL
Effects of PGC-1␣ on Glucose Utilization and Lipid
Metabolism
Experimental studies to examine the role of PGC-1␣ in
insulin sensitivity have been conducted in cell lines and in
PGC-1␣-KO and -overexpressing mice. In general, these studies, except for a report in muscle cells (132), have yielded
unexpected results (Table 2).
Cell lines. In L6 and C2C12 myotubes, but not in the COS-1
kidney epithelial cell line, PGC-1␣ overexpression increased
insulin-stimulated glucose transport largely via an increase in
GLUT4 expression through a PGC-1␣ and MEF2C interaction
at the promoter of GLUT4 (132). This study forged the notion
that PGC-1␣ can have insulin-sensitizing effects.
PGC-1␣-null mice. Two models of PGC-1␣-null mice have
been created (111, 117). In one model the expression of
selected mitochondrial genes was reduced by 20 –50% (117),
but surprisingly, the animals were hyperactive, possibly accounting for their unexpected lean phenotype (6, 117). Other
PGC-1␣-null mice were not hyperactive (111) and exhibited
most of the expected metabolic changes, including 1) abnormally increased body fat (only in female mice), 2) diminished
mitochondrial number and respiratory capacity of soleus muscle, 3) reduced muscle performance and exercise capacity, and
4) short-term, starvation-induced hepatic steatosis (111). Yet,
contrary to the expectation that the PGC-1␣-null mice were
susceptible to insulin resistance, both models were resistant to
diet-induced obesity (111, 117).
Muscle-specific PGC-1␣-null mice. Muscle-specific PGC1␣-KO mice exhibited the expected reductions in selected
mitochondrial genes (73). Moreover, the animals were hypoactive and exercise intolerant (70, 73). PGC-1␣ ablation provoked a reduction in GLUT4 mRNA, yet surprisingly, peripheral (i.e., muscle) insulin sensitivity and Akt activity were
increased (71).
PGC-1␣-overexpressing mice. In PGC-1␣-transgenic mice
there was the expected increase in selected mitochondrial
genes, a robust increase in mitochondrial proliferation in muscle (116) and heart (109, 173), and a resistance to muscle
fatigue (116). However, anomalies were also reported, including the loss of cardiac sarcomeric structure due to excess
mitochondria (109, 173). Moreover, whereas a lean phenotype
was expected, these animals were severely obese (109). In
addition, neither the expected increase in GLUT4 expression
nor the expected increase in insulin-stimulated glucose transport was observed. Instead, a ⬎10-fold increase in PGC-1␣
mRNA unexpectedly reduced GLUT4 mRNA and whole body
insulin sensitivity (133).
Muscle-specific PGC-1␣ overexpression. Limiting PGC-1␣
overexpression to skeletal muscle also induced deleterious
effects. These muscle-specific PGC-1␣-overexpressing mice
were not protected from diet-induced insulin resistance as had
been expected. Instead, these mice developed insulin resistance
when provided with a high-fat diet (39). This was attributed to
reduced peripheral (muscle) insulin sensitivity (⫺25%) and
299 • AUGUST 2010 •
www.ajpendo.org
Downloaded from ajpendo.physiology.org on February 26, 2011
Given 1) the linkage between the dysregulation in fatty acid
metabolism and impairment in insulin sensitivity and 2) that
PGC-1␣ induces mitochondrial biogenesis (cf. Ref. 73) and the
expression of key enzymes involved in skeletal muscle fatty
acid utilization (for review, see Refs. 16, 73, and 113), it was
of considerable interest to examine whether PGC-1␣ expression was altered in type 2 diabetes.
Oxidative phosphorylation genes and PGC-1␣ are reduced
in type 2 diabetes. Based on multiple statistical comparisons of
high-density oligonucleotide arrays and quantitative real-time
PCR, it has been concluded that differences in muscle gene
expression between type 2 diabetes patients and healthy humans are quite modest (i.e., ⱕ34% reduction in type 2 diabetes), involving only a small number of selected genes in fatty
acid transport and metabolism and oxidative phosphorylation
(OXPHOS) (137, 148). Concurrently, PGC-1␣ mRNA expression was also reduced modestly (20 –36%) in muscles of type
2 diabetes patients (137, 148) as well as in asymptomatic
individuals with a family history of type 2 diabetes (⫺34%)
(148). Reductions in PGC-1␣ have also been observed when
fasting insulin concentrations are increased and with an increased body mass index in diabetes-prone humans (8, 155).
Thus, there appears to be a potential role for PGC-1␣ in the
etiology of insulin resistance in human skeletal muscle. This
linkage is strengthened by the fact that 1) PGC-1␣ is also
downregulated in selected animal models of insulin resistance
and type 2 diabetes (99, 189), 2) PGC-1␣ is known to regulate
genes involved in lipid metabolism and OXPHOS (cf. Ref. 16,
73, and 113), and 3) PGC-1␣ transfection in a mouse skeletal
muscle cell line upregulated almost precisely a subset of
OXPHOS genes that were downregulated in muscles of type 2
diabetes patients (137). Importantly, in type 2 diabetes, the
reductions in the expression of skeletal muscle PGC-1␣ and its
associated OXPHOS genes were quite modest (ⱕ34%) (137,
148). This suggests that a modest increase in PGC-1␣ may be
sufficient to improve insulin sensitivity.
Does the reduction in PGC-1␣ in type 2 diabetes reflect
reduced muscle activity? To date, little recognition has been
given to the fact that reductions in PGC-1␣ and its associated
OXPHOS genes could be spuriously associated with type 2
diabetes. Individuals with type 2 diabetes have low levels of
physical activity (76, 180), and PGC-1␣ and OXPHOS genes
are downregulated, when physical activity is reduced (59, 172,
204). Indeed, there is a highly significant positive relationship
between maximal aerobic capacity (V̇O2max; an index of low
physical activity) and the expression of OXPHOS genes among
individuals with type 2 diabetes and those with normal and
impaired glucose tolerance (137). Close inspection of these
data revealed that individuals with type 2 diabetes had a 25%
lower V̇O2max and were clustered in the lowest third of the
correlational analysis (OXPHOS vs. V̇O2max). Others have
shown that PGC-1␣ mRNA and its associated genes are positively correlated with V̇O2max (59) and that “diabetes-like”
reductions in PGC-1␣ mRNA are induced by muscle inactivity
(204). Thus, it is unclear to what extent the observed reductions
in skeletal muscle PGC-1␣ mRNA and its associated OXPHOS
genes in type 2 diabetes (137, 148) are 1) the result of type 2
diabetes per se or 2) due to reduced physical activity patterns
in individuals with type 2 diabetes.
299 • AUGUST 2010 •
www.ajpendo.org
†Reduced
†No
†Severely (Ref. 109)
Increased
†Increased
†No difference
No difference
No difference
公Large increasec
公Increasedc
公Increased
Increased
Increased
No difference
Reduced
Increased
†Reduced
公Reduced
†Reduceda
†Reduceda
†Reduceda
Muscle specific (600%),
Ref. 39
No difference
Increased
†Reduced
†Intolerant
Whole body (1,000–2,000%),
Refs. 109, 133
No difference
†Intoleranta
Improved
Muscle specific,
Ref. 71**
公Increased
公Increasedd,e,
公Increased
公Increasede
公Increasedc
公Decreased
公Increasedc
公Decreased
Increased
Increased
Increased
No difference
No difference
公Increased
公Increased
Zucker obese muscle (25%),
Ref. 14
Increased
Increased
公Increased
No difference
No difference
No difference
No difference
公Increased
Healthy muscle (25%),
Ref. 15
Modest (25%) Muscle-Specific PGC-1␣ Overexpression
IRS-1, insulin receptor substrate-1; PI, phosphatidylinositol; ACC2, acetyl-CoA carboxylase-2; mtGPAT, mitochondrial glycerol-3-phosphate acyltransferase-1; DGAT1, diacylglycerol acyltransferase 1.
Comparisons are relative to wild-type mice or muscles not transfected with PGC-1␣. 公Response observed is the expected response in the PGC-1␣ model. †Response observed is contrary to the expected
response in the PGC-1␣ model. *PGC-1␣-null mice in Ref. 117 are hyperactive and exhibit neurological disorders characteristic of Huntington’s disease. **PGC-1␣ muscle-specific null mice in Ref. 71 are
hypoactive. ***Results are observed primarily in female mice. aObservations after a period of high-fat feeding; bfatty acid oxidation was improved in subsarcolemma mitochondria only, not in intramyofibrillar
mitochondria; cmRNA; dprotein; eactivity.
†No (Ref. 117)
公Yes (Ref.
111)***
†Improveda
†Improveda
Whole body,
Refs. 111, 117*
Large (600–2,000%) PGC-1␣ Overexpression
PGC-1␣, EXERCISE TRAINING, AND INSULIN SENSITIVITY
Downloaded from ajpendo.physiology.org on February 26, 2011
AJP-Endocrinol Metab • VOL
Fat mass
Glucose metabolism
Insulin sensitivity
Glucose tolerance
Peripheral glucose flux
Muscle glucose transport
Protein expression
Muscle GLUT4
Muscle IRS-1
Muscle PI 3-kinase
Muscle Akt2 protein
Muscle AS160 protein
Insulin signaling
Muscle p-IRS-1
Muscle p-Akt or activity
Muscle p-AS160
Lipid metabolism
Fatty acid oxidation
Intramuscular lipids
Lipid metabolism gene
AMPK␣2 protein
p-AMPK␣2 or activity
CD36 mRNA/protein
CPT I mRNA, protein or activity
ACC2 protein
mtGPAT mRNA
DGAT1 mRNA
Diet-induced obesity
Metabolic Parameter
PGC-1␣-Null
Table 2. Comparison of glucose and lipid metabolism responses in different models of PGC-1␣ ablation and overexpression
Review
E153
Review
E154
PGC-1␣, EXERCISE TRAINING, AND INSULIN SENSITIVITY
impaired muscle insulin-stimulated glucose transport, insulin
receptor substrate-1 (IRS-1) phosphorylation, and Akt2 activity (39). Concurrently, there were increases in selected genes
regulating lipid metabolism as well as in functional measurements of muscle fatty acid metabolism, including fatty acid
oxidation (⫹30%), and 200 –300% increases in intramuscular
lipids (triacylglycerol, diacylglycerol, lysophosphatidic acid,
long-chain fatty acyl-CoA) (39), which have been implicated
in interfering with insulin signaling.
Are PGC-1␣-Null and -Transgenic Animals Suitable for
Revealing PGC-1␣ Insulin-Sensitizing Effects In Vivo?
An Alternative Approach: PGC-1␣ Overexpression Within
Physiological Limits
Since traditional genetic approaches, including insulin sensitivity, may not be suitable for examining the role of PGC-1␣ in
muscle metabolism, another strategy has evolved. This approach
aimed to 1) upregulate PGC-1␣ modestly and 2) mimic physioAJP-Endocrinol Metab • VOL
Overexpressing PGC-1␣ Within a Physiological Range
Improves Lipid Metabolism and Glucose Transport in
Healthy and Insulin-Resistant Muscle
When PGC-1␣ was modestly overexpressed (⬃25%) in rat
muscle (15), using an electrotransfection approach (17, 40,
144), PGC-1␣ mRNA (28%) and protein (24%) were modestly
upregulated (15). Typically, only 30 – 40% of the muscle fibers
are electrotransfected (15, 17, 26, 40, 144, 178). Hence,
PGC-1␣ upregulation in the transfected muscle fibers was
60 –75%, which is within a physiological range. This level of
PGC-1␣ overexpression is accompanied by a visible increase
in the capacity for oxidative metabolism, namely, the redder
coloration of PGC-1␣-transfected muscle [see Fig. 5 in Benton
et al. (15)].
The modest or physiological overexpression of PGC-1␣
induced a number of positive metabolic changes in healthy
animals, including improvements in insulin-stimulated glucose
transport, mitochrondrial fatty acid oxidation (subsarcolemmal
mitchondria only, not intermyofibrillar mitochondria), and mitochondrial density (15). These changes were accompanied by
PGC-1␣-induced upregulation of some proteins (FAT/CD36,
GLUT4, AMPK␣2), but not others (plasma membrane-associated fatty acid binding protein, IRS-1, phosphatidylinositol 3-kinase, Akt2, hormone-sensitive lipase), improvements in insulinstimulated phosphorylation of Akt2, and increased expression of
COX IV and FAT/CD36 in isolated mitochondria (15). Similarly,
Fig. 2. Comparison between relative changes in PGC-1␣ overexpression (%)
and changes in insulin-stimulated glucose utilization (%) in healthy animals.
These data suggest that when PGC-1␣ expression is more than doubled (i.e.,
⬎100% increase), insulin-stimulated glucose utilization deteriorates sufficiently to result in insulin resistance (gray box). In contrast, increasing
PGC-1␣ expression more modestly (⬍100%) increases insulin sensitivity
(dotted box). These contrasting responses may reflect, in part, the differential
effects of PGC-1␣, depending on its level of overexpression, on intramuscular
bioactive lipid accumulation that can interfere with insulin signaling. Data are
from Refs. 14, 15, 39, 112, and 133, in which PGC-1␣ was overexpressed to
varying levels in transgenic animals or in electrotransfected muscles. PGC-1␣
mRNA increase (%) was calculated relative to controls in these studies.
Insulin-stimulated glucose utilization was based on various methods, and the
increase (%) was calculated relative to controls.
299 • AUGUST 2010 •
www.ajpendo.org
Downloaded from ajpendo.physiology.org on February 26, 2011
Based on the foregoing studies with PGC-1␣ ablation or
overexpression, it appears that 1) PGC-1␣ does not contribute
to regulating insulin sensitivity. However, this contrasts with
2) experiments in muscle cells in which GLUT4 and insulin
signaling were increased by PGC-1␣ (132) and 3) gene array
data in human type 2 diabetes (137, 148) in which reductions
in muscle PGC-1␣ expression have been interpreted as evidence that PGC-1␣ has a role in regulating insulin sensitivity.
Taken altogether these observations may suggest that 1) the
associative evidence between reductions in PGC-1␣ and type 2
diabetes in humans cannot be interpreted causally or, 2) alternatively, the use of genetic approaches, rather than physiological/metabolic considerations, for examining the insulin-sensitizing role of PGC-1␣ in vivo may have inadvertently obscured
the positive metabolic effects of this coactivator.
In recent years, genetically altered animal models have
proved to be extremely useful to examine the function of
specific genes, particularly those with a specific restrictive
function dedicated to a single process. However, genes involved in broader metabolic functions and actions in multiple
tissues have, not unexpectedly, led to unanticipated results
(e.g., various murine PPAR␥ models) (for review, see Ref. 42).
Hence, the appropriateness of PGC-1␣-null or -overexpressing
animal models to examine insulin sensitivity (39, 71, 109, 111,
117, 133) may be questioned, given the multiple metabolic
effects induced by this coactivator among and within tissues.
Viewed from a physiological perspective, it is not entirely
surprising that completely ablating or massively overexpressing PGC-1␣ has consistently provided unexpected results with
respect to establishing a role for PGC-1␣ in improving insulin
sensitivity in vivo (Table 2). PGC-1␣ overexpression by 600 –
2,000% (39, 133) is physiologically unrealistic, exceeding by
five- to 10-fold the changes that can be expected to be induced
in muscle by physiological stimuli such as cold exposure (146),
acute exercise (200, 223), or exercise training (3, 189, 198).
Just as studies with PPAR␥ animal models have shown that too
much of a good thing causes harm (42), this may also apply to
PGC-1␣. Indeed, there is now ample evidence that a massive
PGC-1␣ overexpression (600 –2,000%) (39, 109, 116, 133,
173) can have unexpected pathophysiological consequences.
logically realistic changes in PGC-1␣ protein expression (i.e.,
20 –150%) (3, 125, 146, 172, 189, 198, 200, 223).
Review
PGC-1␣, EXERCISE TRAINING, AND INSULIN SENSITIVITY
Comparing PGC-1␣ Overexpression With Improvements in
Glucose Utilization
The effects of PGC-1␣ overexpression on insulin sensitivity
in vivo can be strikingly different. When PGC-1␣ overexpression is within a physiological range (⬍100%), improvements
in insulin sensitivity are observed (Table 2 and Fig. 2). However, when muscle-specific PGC-1␣ overexpression is far beyond normal physiological limits, insulin-stimulated glucose
disposal is impaired (Fig. 2). Although this relationship between PGC-1␣ overexpression and insulin-stimulated glucose
utilization (Fig. 2) does not reflect the complexity of PGC-1␣’s
effects or its mechanisms of action, this relationship (Fig. 2)
does provide insight as to when PGC-1␣ upregulation is likely
to be most effective.
Speculation Concerning Disparate Effects of
PGC-1␣-Mediated Glucose Utilization
Disparate changes in PGC-1␣-mediated glucose utilization
may be linked, in part, to the differential PGC-1␣-induced
upregulation of proteins involved with lipid metabolism. Key
among these is the fatty acid transporter FAT/CD36. This
PGC-1␣-inducible gene (15, 39) has been linked to insulin
resistance (21, 23, 62, 83), since it promotes excess uptake of
fatty acids beyond the capacity to oxidize them (21, 23, 62, 83).
Hence, intramuscular lipids accumulate. Because of this work,
we (15, 16) had already suggested several years ago that it may
be critically important to limit the PGC-1␣-induced overexpression of FAT/CD36, even in the face of PGC-1␣-induced
improvements in fatty acid oxidation. Indeed, an excessively
large PGC-1␣ overexpression (⫹600%) induced a large upregulation of FAT/CD36 (⫹300%) (39), which not unexpectAJP-Endocrinol Metab • VOL
edly increased intramuscular lipids by 200 –300% and therefore likely reduced insulin-stimulated glucose transport and
activation of insulin-signaling proteins (39). In contrast, modest PGC-1␣ overexpression only moderately increased FAT/
CD36 (20 –35%) in muscle (Table 2) (14, 15), an increase that
may be expected to improve fatty acid oxidation while not
increasing intramuscular lipids (144). Thus, it seems that if
PGC-1␣ is to be a therapeutic target, its upregulation in muscle
must be modest, since this limits PGC-1␣-induced FAT/CD36
upregulation, thereby preventing excess fatty acid uptake and
intramuscular lipid accumulation.
Summary
Multiple signaling transduction pathways, including Ca2⫹dependent signaling, ROS, NO, AMPK, and p38 MAPK, have
been linked to the regulation of PGC-1␣ expression and function in skeletal muscle plasticity. Gene deletion studies have
demonstrated that the CnA/NFAT signaling controls fiber type
transformation, whereas p38␥ MAPK/PGC-1␣ signaling controls mitochondrial biogenesis and angiogenesis in response to
endurance exercise in skeletal muscle. The insulin-sensitizing
effects of exercise may be mediated, in part, via the exerciseinduced upregulation of PGC-1␣, since its modest overexpression within an exercise-like range is sufficient to improve both
lipid metabolism and insulin sensitivity.
GRANTS
These studies were supported in part by grants from the National Institute
of Arthritis and Musculoskeletal and Skin Diseases (RO1-AR-050429 to Z.
Yan) and the Natural Sciences and Engineering Research Council of Canada
(A. Bonen), the Canadian Institutes of Health Research (A. Bonen), and the
Canada Research Chair program (A. Bonen) A. Bonen is the Canada Research
Chair in Metabolism and Health.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
REFERENCES
1. Adhihetty PJ, Uguccioni G, Leick L, Hidalgo J, Pilegaard H, Hood
DA. The role of PGC-1␣ on mitochondrial function and apoptotic
susceptibility in muscle. Am J Physiol Cell Physiol 297: C217–C225,
2009.
2. Akimoto T, Li P, Yan Z. Functional interaction of regulatory factors
with the Pgc-1␣ promoter in response to exercise by in vivo imaging. Am
J Physiol Cell Physiol 295: C288 –C292, 2008.
3. Akimoto T, Pohnert SC, Li P, Zhang M, Gumbs C, Rosenberg PB,
Williams RS, Yan Z. Exercise stimulates Pgc-1alpha transcription in
skeletal muscle through activation of the p38 MAPK pathway. J Biol
Chem 280: 19587–19593, 2005.
4. Akimoto T, Ribar TJ, Williams RS, Yan Z. Skeletal muscle adaptation
in response to voluntary running in Ca2⫹/calmodulin-dependent protein
kinase IV-deficient mice. Am J Physiol Cell Physiol 287: C1311–C1319,
2004.
5. Arany Z, Foo SY, Ma Y, Ruas JL, Bommi-Reddy A, Girnun G,
Cooper M, Laznik D, Chinsomboon J, Rangwala SM, Baek KH,
Rosenzweig A, Spiegelman BM. HIF-independent regulation of VEGF
and angiogenesis by the transcriptional coactivator PGC-1alpha. Nature
451: 1008 –1012, 2008.
6. Arany Z, He H, Lin J, Hoyer K, Handschin C, Toka O, Ahmad F,
Matsui T, Chin S, Wu PH, Rybkin II, Shelton JM, Manieri M, Cinti
S, Schoen FJ, Bassel-Duby R, Rosenzweig A, Ingwall JS, Spiegelman
BM. Transcriptional coactivator PGC-1 alpha controls the energy state
and contractile function of cardiac muscle. Cell Metab 1: 259 –271, 2005.
7. Arany Z, Lebrasseur N, Morris C, Smith E, Yang W, Ma Y, Chin S,
Spiegelman BM. The transcriptional coactivator PGC-1beta drives the
299 • AUGUST 2010 •
www.ajpendo.org
Downloaded from ajpendo.physiology.org on February 26, 2011
PGC-1␣ upregulation (20 –27%) in insulin-resistant muscles
(obese Zucker rats) (14) improved insulin-stimulated glucose
transport, reduced intramuscular lipids (triacylglycerol, diacylglycerol, ceramide), increased mitochondrial fatty acid oxidation
(subsarcolemmal mitochondria only, not intermyofibrillar mitochondria), and increased expression of FAT/CD36 and GLUT4,
but not Akt2 or AS160, although their insulin-stimulated phosphorylation was increased (14). Modest PGC-1␣ overexpression
also protected animals from diet-induced insulin resistance
(Bonen A, unpublished data).
For all parameters examined, whether in healthy or insulinresistant animals, the PGC-1␣-induced alterations in selected
parameters ranged from 15 to 85%, with most being in the
range of 20 to 50%. Although these responses are not large
when compared against those that can be induced in transgenic
animals, these increases are metabolically meaningful, because
in skeletal muscle of type 2 diabetic patients there are only
1) small reductions in PGC-1␣ (ⱕ36%) (137, 148) and 2) a
small number of selected genes involved in fatty acid transport
and metabolism and in OXPHOS (ⱕ34%) (137, 148). Moreover, unlike with massive PGC-1␣ overexpression (Table 2),
the changes with modest PGC-1␣ overexpression in all of the
parameters collectively provide a metabolically coordinated
response in lipid and carbohydrate metabolism such that insulin sensitivity was improved (Table 2) (14, 15). Thus, experiments based on physiological and metabolic rationales for
controlling the overexpression of PGC-1␣ have demonstrated
the insulin-sensitizing effects of this coactivator.
E155
Review
E156
8.
9.
10.
11.
12.
13.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
formation of oxidative type IIX fibers in skeletal muscle. Cell Metab 5:
35–46, 2007.
Araya R, Blangero J, Almasy L, O’Connell P, Stern M, Duggirala R.
A major locus for body mass index (BMI) on chromosome 4p in Mexican
Americans (Abstract). Obes Res 9: 70S, 2001.
Aronson D, Boppart MD, Dufresne SD, Fielding RA, Goodyear LJ.
Exercise stimulates c-Jun NH2 kinase activity and c-Jun transcriptional
activity in human skeletal muscle. Biochem Biophys Res Commun 251:
106 –110, 1998.
Aronson D, Violan MA, Dufresne SD, Zangen D, Fielding RA,
Goodyear LJ. Exercise stimulates the mitogen-activated protein kinase
pathway in human skeletal muscle. J Clin Invest 99: 1251–1257, 1997.
Baar K, Wende AR, Jones TE, Marison M, Nolte LA, Chen M, Kelly
DP, Holloszy JO. Adaptations of skeletal muscle to exercise: rapid
increase in the transcriptional coactivator PGC-1. FASEB J 16: 1879 –
1886, 2002.
Bajaj M, Medina-Navarro R, Suraamornkul S, Meyer C, DeFronzo
RA, Mandarino LJ. Paradoxical changes in muscle gene expression in
insulin-resistant subjects after sustained reduction in plasma free fatty
acid concentration. Diabetes 56: 743–752, 2007.
Balon TW, Nadler JL. Nitric oxide release is present from incubated
skeletal muscle preparations. J Appl Physiol 77: 2519 –2521, 1994.
Benton CR, Holloway GP, Han XX, Yoshida Y, Snook LA, Lally J,
Glatz JFC, Luiken JJ, Chabowski A, Bonen A. PGC-1␣ overexpression improves lipid utilization, insulin signalling, and glucose transport
in skeletal muscle of lean and insulin resistant obese Zucker rats.
Diabetologia. In press.
Benton CR, Nickerson JG, Lally J, Han XX, Holloway GP, Glatz JF,
Luiken JJ, Graham TE, Heikkila JJ, Bonen A. Modest PGC-1alpha
overexpression in muscle in vivo is sufficient to increase insulin sensitivity and palmitate oxidation in subsarcolemmal, not intermyofibrillar,
mitochondria. J Biol Chem 283: 4228 –4240, 2008.
Benton CR, Wright DC, Bonen A. PGC-1alpha-mediated regulation of
gene expression and metabolism: implications for nutrition and exercise
prescriptions. Appl Physiol Nutr Metab 33: 843–862, 2008.
Benton CR, Yoshida Y, Lally J, Han XX, Hatta H, Bonen A. PGC-1␣
increases skeletal muscle lactate uptake by increasing the expression of
MCT1 but not MCT2 or MCT4. Physiol Genomics 35: 45–54, 2008.
Boden G. Free fatty acids, insulin resistance, and type 2 diabetes
mellitus. Proc Assoc Am Physicians 111: 241–248, 1999.
Boden G, Chen X, Iqbal N. Acute lowering of plasma fatty acids lowers
basal insulin secretion in diabetic and nondiabetic subjects. Diabetes 47:
1609 –1612, 1998.
Boden G, Jadali F, White J, Liang Y, Mozzoli M, Chen X, Coleman
E, CS. Effects of fat on insulin-stimulated carbohydrate metabolism in
normal men. J Clin Invest 88: 960 –966, 1991.
Bonen A, Chabowski A, Luiken JJ, Glatz JF. Is membrane transport
of FFA mediated by lipid, protein, or both? Mechanisms and regulation
of protein-mediated cellular fatty acid uptake: molecular, biochemical,
and physiological evidence. Physiology (Bethesda) 22: 15–29, 2007.
Bonen A, Dohm GL, van Loon LJ. Lipid metabolism, exercise and
insulin action. Essays Biochem 42: 47–59, 2006.
Bonen A, Parolin ML, Steinberg GR, Calles-Escandon J, Tandon
NN, Glatz JF, Luiken JJ, Heigenhauser GJ, Dyck DJ. Triacylglycerol
accumulation in human obesity and type 2 diabetes is associated with
increased rates of skeletal muscle fatty acid transport and increased
sarcolemmal FAT/CD36. FASEB J 18: 1144 –1146, 2004.
Bonen A, Tan MH, Watson-Wright WM. Effects of exercise on insulin
binding and glucose metabolism in muscle. Can J Physiol Pharmacol 62:
1500 –1504, 1984.
Bruce CR, Anderson MJ, Carey AL, Newman DG, Bonen A, Kriketos AD, Cooney GJ, Hawley JA. Muscle oxidative capacity is a better
predictor of insulin sensitivity than lipid status. J Clin Endocrinol Metab
88: 5444 –5451, 2003.
Bruce CR, Hoy AJ, Turner N, Watt MJ, Allen TL, Carpenter K,
Cooney GJ, Febbraio MA, Kraegen EW. Overexpression of carnitine
palmitoyltransferase-1 in skeletal muscle is sufficient to enhance fatty
acid oxidation and improve high-fat diet-induced insulin resistance.
Diabetes 58: 550 –558, 2009.
Bruce CR, Thrush AB, Mertz VA, Bezaire V, Chabowski A, Heigenhauser GJ, Dyck DJ. Endurance training in obese humans improves
glucose tolerance and mitochondrial fatty acid oxidation and alters
muscle lipid content. Am J Physiol Endocrinol Metab 291: E99 –E107,
2006.
AJP-Endocrinol Metab • VOL
28. Calvo JA, Daniels TG, Wang X, Paul A, Lin J, Spiegelman BM,
Stevenson SC, Rangwala SM. Muscle-specific expression of PPAR␥
coactivator-1␣ improves exercise performance and increases peak oxygen uptake. J Appl Physiol 104: 1304 –1312, 2008.
29. Cantó C, Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L, Milne
JC, Elliott PJ, Puigserver P, Auwerx J. AMPK regulates energy
expenditure by modulating NAD⫹ metabolism and SIRT1 activity.
Nature 458: 1056 –1060, 2009.
30. Cantó C, Jiang LQ, Deshmukh AS, Mataki C, Coste A, Lagouge M,
Zierath JR, Auwerx J. Interdependence of AMPK and SIRT1 for
metabolic adaptation to fasting and exercise in skeletal muscle. Cell
Metab 11: 213–219, 2010.
31. Cao W, Daniel KW, Robidoux J, Puigserver P, Medvedev AV, Bai X,
Floering LM, Spiegelman BM, Collins S. p38 mitogen-activated protein kinase is the central regulator of cyclic AMP-dependent transcription
of the brown fat uncoupling protein 1 gene. Mol Cell Biol 24: 3057–3067,
2004.
32. Chavez JA, Holland WL, Bar J, Sandhoff K, Summers SA. Acid
ceramidase overexpression prevents the inhibitory effects of saturated
fatty acids on insulin signaling. J Biol Chem 280: 20148 –20153, 2005.
33. Chavez JA, Knotts TA, Wang LP, Li G, Dobrowsky RT, Florant GL,
Summers SA. A role for ceramide, but not diacylglycerol, in the
antagonism of insulin signal transduction by saturated fatty acids. J Biol
Chem 278: 10297–10303, 2003.
34. Chen ZP, McConell GK, Michell BJ, Snow RJ, Canny BJ, Kemp BE.
AMPK signaling in contracting human skeletal muscle: acetyl-CoA
carboxylase and NO synthase phosphorylation. Am J Physiol Endocrinol
Metab 279: E1202–E1206, 2000.
35. Chen ZP, Mitchelhill KI, Michell BJ, Stapleton D, Rodriguez-Crespo
I, Witters LA, Power DA, Ortiz de Montellano PR, Kemp BE.
AMP-activated protein kinase phosphorylation of endothelial NO synthase. FEBS Lett 443: 285–289, 1999.
36. Chin ER. The role of calcium and calcium/calmodulin-dependent kinases in skeletal muscle plasticity and mitochondrial biogenesis. Proc
Nutr Soc 63: 279 –286, 2004.
37. Chin ER, Olson EN, Richardson JA, Yang Q, Humphries C, Shelton
JM, Wu H, Zhu W, Bassel-Duby R, Williams RS. A calcineurindependent transcriptional pathway controls skeletal muscle fiber type.
Genes Dev 12: 2499 –2509, 1998.
38. Chinsomboon J, Ruas J, Gupta RK, Thom R, Shoag J, Rowe GC,
Sawada N, Raghuram S, Arany Z. The transcriptional coactivator
PGC-1alpha mediates exercise-induced angiogenesis in skeletal muscle.
Proc Natl Acad Sci USA 106: 21401–21406, 2009.
39. Choi CS, Befroy DE, Codella R, Kim S, Reznick RM, Hwang YJ, Liu
ZX, Lee HY, Distefano A, Samuel VT, Zhang D, Cline GW, Handschin C, Lin J, Petersen KF, Spiegelman BM, Shulman GI. Paradoxical effects of increased expression of PGC-1alpha on muscle mitochondrial function and insulin-stimulated muscle glucose metabolism. Proc
Natl Acad Sci USA 105: 19926 –19931, 2008.
40. Clarke DC, Miskovic D, Han XX, Calles-Escandon J, Glatz JF,
Luiken JJ, Heikkila JJ, Bonen A. Overexpression of membraneassociated fatty acid binding protein (FABPpm) in vivo increases fatty
acid sarcolemmal transport and metabolism. Physiol Genomics 17: 31–
37, 2004.
41. Close GL, Ashton T, McArdle A, Jackson MJ. Microdialysis studies of
extracellular reactive oxygen species in skeletal muscle: factors influencing the reduction of cytochrome c and hydroxylation of salicylate. Free
Radic Biol Med 39: 1460 –1467, 2005.
42. Cock TA, Houten SM, Auwerx J. Peroxisome proliferator-activated
receptor-gamma: too much of a good thing causes harm. EMBO Rep 5:
142–147, 2004.
43. Coggan AR, Spina RJ, King DS, Rogers MA, Brown M, Nemeth PM,
Holloszy JO. Skeletal muscle adaptations to endurance training in 60- to
70-yr-old men and women. J Appl Physiol 72: 1780 –1786, 1992.
44. Coll T, Jové M, Rodríguez-Calvo R, Eyre E, Palomer X, Sánchez
RM, Merlos M, Laguna JC, Vázquez-Carrera M. Palmitate-mediated
downregulation of peroxisome proliferator-activated receptor-gamma coactivator 1alpha in skeletal muscle cells involves MEK1/2 and nuclear
factor-kappaB activation. Diabetes 55: 2779 –2787, 2006.
45. Costford SR, Bajpeyi S, Pasarica M, Albarado DC, Thomas SC, Xie
H, Church TS, Jubrias SA, Conley KE, Smith SR. Skeletal muscle
NAMPT is induced by exercise in humans. Am J Physiol Endocrinol
Metab 298: E117–E126, 2010.
299 • AUGUST 2010 •
www.ajpendo.org
Downloaded from ajpendo.physiology.org on February 26, 2011
14.
PGC-1␣, EXERCISE TRAINING, AND INSULIN SENSITIVITY
Review
PGC-1␣, EXERCISE TRAINING, AND INSULIN SENSITIVITY
AJP-Endocrinol Metab • VOL
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
signaling pathways in rat skeletal muscle. Am J Physiol Endocrinol
Metab 271: E403–E408, 1996.
Goto M, Terada S, Kato M, Katoh M, Yokozeki T, Tabata I,
Shimokawa T. cDNA cloning and mRNA analysis of PGC-1 in epitrochlearis muscle in swimming exercised rats. Biochem Biophys Res
Commun 274: 350 –354, 2000.
Hancock CR, Han DH, Chen M, Terada S, Yasuda T, Wright DC,
Holloszy JO. High-fat diets cause insulin resistance despite an increase
in muscle mitochondria. Proc Natl Acad Sci USA 105: 7815–7820, 2008.
Hancock CR, Janssen E, Terjung RL. Contraction-mediated phosphorylation of AMPK is lower in skeletal muscle of adenylate kinasedeficient mice. J Appl Physiol 100: 406 –413, 2006.
Handschin C, Chin S, Li P, Liu F, Maratos-Flier E, Lebrasseur NK,
Yan Z, Spiegelman BM. Skeletal muscle fiber-type switching, exercise
intolerance, and myopathy in PGC-1alpha muscle-specific knock-out
animals. J Biol Chem 282: 30014 –30021, 2007.
Handschin C, Choi CS, Chin S, Kim S, Kawamori D, Kurpad AJ,
Neubauer N, Hu J, Mootha VK, Kim YB, Kulkarni RN, Shulman GI,
Spiegelman BM. Abnormal glucose homeostasis in skeletal musclespecific PGC-1alpha knockout mice reveals skeletal muscle-pancreatic
beta cell crosstalk. J Clin Invest 117: 3463–3474, 2007.
Handschin C, Rhee J, Lin J, Tarr PT, Spiegelman BM. An autoregulatory loop controls peroxisome proliferator-activated receptor gamma
coactivator 1alpha expression in muscle. Proc Natl Acad Sci USA 100:
7111–7116, 2003.
Handschin C, Spiegelman BM. Peroxisome proliferator-activated receptor gamma coactivator 1 coactivators, energy homeostasis, and metabolism. Endocr Rev 27: 728 –735, 2006.
Hardie DG. Minireview: the AMP-activated protein kinase cascade: the
key sensor of cellular energy status. Endocrinology 144: 5179 –5183,
2003.
Hashimoto T, Hussien R, Oommen S, Gohil K, Brooks GA. Lactate
sensitive transcription factor network in L6 cells: activation of MCT1 and
mitochondrial biogenesis. FASEB J 21: 2602–2612, 2007.
Hays LM, Clark DO. Correlates of physical activity in a sample of older
adults with type 2 diabetes. Diabetes Care 22: 706 –712, 1999.
Heath GW, Gavin JR, Hinderliter JM, Hagberg JM, Bloomfield SA,
Holloszy JO. Effects of exercise and lack of exercise on glucose
tolerance and insulin sensitivity. J Appl Physiol 55: 512–517, 1983.
Henriksen EJ. Invited review: Effects of acute exercise and exercise
training on insulin resistance. J Appl Physiol 93: 788 –796, 2002.
Henriksen EJ, Bourey RE, Rodnick KJ, Koranyi L, Permutt MA,
Holloszy JO. Glucose transporter protein content and glucose transport
capacity in rat skeletal muscles. Am J Physiol Endocrinol Metab 259:
E593–E598, 1990.
Holland WL, Brozinick JT, Wang LP, Hawkins ED, Sargent KM,
Liu Y, Narra K, Hoehn KL, Knotts TA, Siesky A, Nelson DH,
Karathanasis SK, Fontenot GK, Birnbaum MJ, Summers SA. Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-,
and obesity-induced insulin resistance. Cell Metab 5: 167–179, 2007.
Holland WL, Knotts TA, Chavez JA, Wang LP, Hoehn KL, Summers SA. Lipid mediators of insulin resistance. Nutr Rev 65: S39 –S46,
2007.
Holloszy JO. Biochemical adaptations in muscle. Effects of exercise on
mitochondrial oxygen uptake and respiratory enzyme activity in skeletal
muscle. J Biol Chem 242: 2278 –2282, 1967.
Holloway GP, Benton CR, Mullen KL, Yoshida Y, Snook LA, Han
XX, Glatz JF, Luiken JJ, Lally J, Dyck DJ, Bonen A. In obese rat
muscle transport of palmitate is increased and is channeled to triacylglycerol storage despite an increase in mitochondrial palmitate oxidation.
Am J Physiol Endocrinol Metab 296: E738 –E747, 2009.
Holloway GP, Bonen A, Spriet LL. Regulation of skeletal muscle
mitochondrial fatty acid metabolism in lean and obese individuals. Am J
Clin Nutr 89: 455S–462S, 2009.
Holloway GP, Perry CG, Thrush AB, Heigenhauser GJ, Dyck DJ,
Bonen A, Spriet LL. PGC-1␣’s relationship with skeletal muscle palmitate oxidation is not present with obesity despite maintained PGC-1␣ and
PGC-1␤ protein. Am J Physiol Endocrinol Metab 294: E1060 –E1069,
2008.
Holloway GP, Thrush AB, Heigenhauser GJ, Tandon NN, Dyck DJ,
Bonen A, Spriet LL. Skeletal muscle mitochondrial FAT/CD36 content
and palmitate oxidation are not decreased in obese women. Am J Physiol
Endocrinol Metab 292: E1782–E1789, 2007.
299 • AUGUST 2010 •
www.ajpendo.org
Downloaded from ajpendo.physiology.org on February 26, 2011
46. Czubryt MP, McAnally J, Fishman GI, Olson EN. Regulation of
peroxisome proliferator-activated receptor gamma coactivator 1 alpha
(PGC-1 alpha) and mitochondrial function by MEF2 and HDAC5. Proc
Natl Acad Sci USA 100: 1711–1716, 2003.
47. Davis BJ, Xie Z, Viollet B, Zou MH. Activation of the AMP-activated
kinase by antidiabetes drug metformin stimulates nitric oxide synthesis in
vivo by promoting the association of heat shock protein 90 and endothelial nitric oxide synthase. Diabetes 55: 496 –505, 2006.
48. DeFronzo RA, Ferrannini E, Sato Y, Felig P, Wahren J. Synergistic
interaction between exercise and insulin on peripheral glucose uptake. J
Clin Invest 68: 1468 –1474, 1981.
49. DeFronzo RA, Jacot E, Jequier E, Maeder E, Wahren J, Felber JP.
The effect of insulin on the disposal of intravenous glucose. Results from
indirect calorimetry and hepatic and femoral venous catheterization.
Diabetes 30: 1000 –1007, 1981.
50. Devlin JT, Hirshman MS, Horton ED, Horton ES. Enhanced peripheral and splanchic insulin sensitivity in NIDDM men after a single bout
of exercise. Diabetes 36: 434 –439, 1987.
51. Drenning JA, Lira VA, Simmons CG, Soltow QA, Sellman JE,
Criswell DS. Nitric oxide facilitates NFAT-dependent transcription in
mouse myotubes. Am J Physiol Cell Physiol 294: C1088 –C1095, 2008.
52. Drenning JA, Lira VA, Soltow QA, Canon CN, Valera LM, Brown
DL, Criswell DS. Endothelial nitric oxide synthase is involved in
calcium-induced Akt signaling in mouse skeletal muscle. Nitric Oxide
21: 192–200, 2009.
53. Eddinger TJ, Moss RL. Mechanical properties of skinned single fibers
of identified types from rat diaphragm. Am J Physiol Cell Physiol 253:
C210 –C218, 1987.
54. Ennion S, Sant’ana Pereira J, Sargeant AJ, Young A, Goldspink G.
Characterization of human skeletal muscle fibres according to the myosin
heavy chains they express. J Muscle Res Cell Motil 16: 35–43, 1995.
55. Fujii N, Hayashi T, Hirshman MF, Smith JT, Habinowski SA,
Kaijser L, Mu J, Ljungqvist O, Birnbaum MJ, Witters LA, Thorell
A, Goodyear LJ. Exercise induces isoform-specific increase in 5=AMPactivated protein kinase activity in human skeletal muscle. Biochem
Biophys Res Commun 273: 1150 –1155, 2000.
56. Fulco M, Sartorelli V. Comparing and contrasting the roles of AMPK
and SIRT1 in metabolic tissues. Cell Cycle 7: 3669 –3679, 2008.
57. Garcia-Roves PM, Huss J, Holloszy JO. Role of calcineurin in exercise-induced mitochondrial biogenesis. Am J Physiol Endocrinol Metab
290: E1172–E1179, 2006.
58. Garcia-Roves PM, Osler ME, Holmstrom MH, Zierath JR. Gain-offunction R225Q mutation in AMP-activated protein kinase gamma3
subunit increases mitochondrial biogenesis in glycolytic skeletal muscle.
J Biol Chem 283: 35724 –35734, 2008.
59. Garnier A, Fortin D, Zoll J, N’Guessan B, Mettauer B, Lampert E,
Veksler V, Ventura-Clapier R. Coordinated changes in mitochondrial
function and biogenesis in healthy and diseased human skeletal muscle.
FASEB J 19: 43–52, 2005.
60. Gaster M, Staehr P, Beck-Nielsen H, Schroder HD, Handberg A.
GLUT4 is reduced in slow muscle fibers of type 2 diabetic patients: is
insulin resistance in type 2 diabetes a slow, type 1 fiber disease? Diabetes
50: 1324 –1329, 2001.
61. Geng T, Li P, Okutsu M, Yin X, Kwek J, Zhang M, Yan Z. PGC-1␣
plays a functional role in exercise-induced mitochondrial biogenesis and
angiogenesis but not fiber-type transformation in mouse skeletal muscle.
Am J Physiol Cell Physiol 298: C572–C579, 2010.
62. Glatz JF, Luiken JJ, Bonen A. Membrane fatty acid transporters as
regulators of lipid metabolism: implications for metabolic disease.
Physiol Rev 90: 367–417, 2010.
63. Gomez-Cabrera MC, Domenech E, Romagnoli M, Arduini A, Borras
C, Pallardo FV, Sastre J, Viña J. Oral administration of vitamin C
decreases muscle mitochondrial biogenesis and hampers training-induced adaptations in endurance performance. Am J Clin Nutr 87: 142–
149, 2008.
64. Goodpaster BH, Brown NF. Skeletal muscle lipid and its association
with insulin resistance: what is the role for exercise? Exerc Sport Sci Rev
33: 150 –154, 2005.
65. Goodpaster BH, Katsiaras A, Kelley DE. Enhanced fat oxidation
through physical activity is associated with improvements in insulin
sensitivity in obesity. Diabetes 52: 2191–2197, 2003.
66. Goodyear LJ, Chang PY, Sherwood DJ, Dufresne SD, Moller DE.
Effects of exercise and insulin on mitogen-activated protein kinase
E157
Review
E158
PGC-1␣, EXERCISE TRAINING, AND INSULIN SENSITIVITY
AJP-Endocrinol Metab • VOL
107.
108.
109.
110.
111.
112.
113.
114.
115.
116.
117.
118.
119.
120.
121.
122.
123.
124.
DM. Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab 7: 45–56, 2008.
Koyama K, Chen G, Lee Y, Unger RH. Tissue tryglycerides, insulin
resistance, and insulin production: implications for hyperinsulinemia of
obesity. Am J Physiol Endocrinol Metab 273: E708 –E713, 1997.
Kressler D, Schreiber SN, Knutti D, Kralli A. The PGC-1-related
protein PERC is a selective coactivator of estrogen receptor alpha. J Biol
Chem 277: 13918 –13925, 2002.
Lehman JJ, Barger PM, Kovacs A, Saffitz JE, Medeiros DM, Kelly
DP. Peroxisome proliferator-activated receptor ␥ coactivator-1 promotes
cardiac mitochondrial biogenesis. J Clin Invest 106: 847–856, 2000.
Leick L, Wojtaszewski JF, Johansen ST, Kiilerich K, Comes G,
Hellsten Y, Hidalgo J, Pilegaard H. PGC-1␣ is not mandatory for
exercise- and training-induced adaptive gene responses in mouse skeletal
muscle. Am J Physiol Endocrinol Metab 294: E463–E474, 2008.
Leone TC, Lehman JJ, Finck BN, Schaeffer PJ, Wende AR, Boudina
S, Courtois M, Wozniak DF, Sambandam N, Bernal-Mizrachi C,
Chen Z, Holloszy JO, Medeiros DM, Schmidt RE, Saffitz JE, Abel
ED, Semenkovich CF, Kelly DP. PGC-1alpha deficiency causes multisystem energy metabolic derangements: muscle dysfunction, abnormal
weight control and hepatic steatosis. PLoS Biol 3: e101, 2005.
Liang H, Balas B, Tantiwong P, Dube J, Goodpaster BH, O’Doherty
RM, Defronzo RA, Richardson A, Musi N, Ward WF. Whole body
overexpression of PGC-1␣ has opposite effects on hepatic and muscle
insulin sensitivity. Am J Physiol Endocrinol Metab 296: E945–E954,
2009.
Lin J, Handschin C, Spiegelman BM. Metabolic control through the
PGC-1 family of transcription coactivators. Cell Metab 1: 361–370,
2005.
Lin J, Puigserver P, Donovan J, Tarr P, Spiegelman BM. Peroxisome
proliferator-activated receptor gamma coactivator 1beta (PGC-1beta), a
novel PGC-1-related transcription coactivator associated with host cell
factor. J Biol Chem 277: 1645–1648, 2002.
Lin J, Tarr PT, Yang R, Rhee J, Puigserver P, Newgard CB,
Spiegelman BM. PGC-1beta in the regulation of hepatic glucose and
energy metabolism. J Biol Chem 278: 30843–30848, 2003.
Lin J, Wu H, Tarr PT, Zhang CY, Wu Z, Boss O, Michael LF,
Puigserver P, Isotani E, Olson EN, Lowell BB, Bassel-Duby R,
Spiegelman BM. Transcriptional co-activator PGC-1 alpha drives the
formation of slow-twitch muscle fibres. Nature 418: 797–801, 2002.
Lin J, Wu PH, Tarr PT, Lindenberg KS, St-Pierre J, Zhang CY,
Mootha VK, Jager S, Vianna CR, Reznick RM, Cui L, Manieri M,
Donovan MX, Wu Z, Cooper MP, Fan MC, Rohas LM, Zavacki AM,
Cinti S, Shulman GI, Lowell BB, Krainc D, Spiegelman BM. Defects
in adaptive energy metabolism with CNS-linked hyperactivity in PGC1alpha null mice. Cell 119: 121–135, 2004.
Ling C, Poulsen P, Carlsson E, Ridderstrale M, Almgren P,
Wojtaszewski J, Beck-Nielsen H, Groop L, Vaag A. Multiple environmental and genetic factors influence skeletal muscle PGC-1alpha and
PGC-1beta gene expression in twins. J Clin Invest 114: 1518 –1526,
2004.
Lira VA, Soltow QA, Long JH, Betters JL, Sellman JE, Criswell DS.
Nitric oxide increases GLUT4 expression and regulates AMPK signaling
in skeletal muscle. Am J Physiol Endocrinol Metab 293: E1062–E1068,
2007.
Listenberger LL, Han X, Lewis SE, Cases S, Farese RV Jr, Ory DS,
Schaffer JE. Triglyceride accumulation protects against fatty acidinduced lipotoxicity. Proc Natl Acad Sci USA 100: 3077–3082, 2003.
Liu C, Li S, Liu T, Borjigin J, Lin JD. Transcriptional coactivator
PGC-1alpha integrates the mammalian clock and energy metabolism.
Nature 447: 477–481, 2007.
Liu L, Shi X, Bharadwaj KG, Ikeda S, Yamashita H, Yagyu H,
Schaffer JE, Yu YH, Goldberg IJ. DGAT1 expression increases heart
triglyceride content but ameliorates lipotoxicity. J Biol Chem 284:
36312–36323, 2009.
Long YC, Glund S, Garcia-Roves PM, Zierath JR. Calcineurin regulates skeletal muscle metabolism via coordinated changes in gene
expression. J Biol Chem 282: 1607–1614, 2007.
Luiken JJ, Arumugam Y, Dyck DJ, Bell RC, Pelsers MM, Turcotte
LP, Tandon NN, Glatz JF, Bonen A. Increased rates of fatty acid
uptake and plasmalemmal fatty acid transporters in obese Zucker rats. J
Biol Chem 276: 40567–40573, 2001.
299 • AUGUST 2010 •
www.ajpendo.org
Downloaded from ajpendo.physiology.org on February 26, 2011
87. Houmard JA. Intramuscular lipid oxidation and obesity. Am J Physiol
Regul Integr Comp Physiol 294: R1111–R1116, 2008.
88. Huss JM, Kopp RP, Kelly DP. Peroxisome proliferator-activated receptor coactivator-1alpha (PGC-1alpha) coactivates the cardiac-enriched
nuclear receptors estrogen-related receptor-alpha and -gamma. Identification of novel leucine-rich interaction motif within PGC-1alpha. J Biol
Chem 277: 40265–40274, 2002.
89. Huss JM, Torra IP, Staels B, Giguere V, Kelly DP. Estrogen-related
receptor alpha directs peroxisome proliferator-activated receptor alpha
signaling in the transcriptional control of energy metabolism in cardiac
and skeletal muscle. Mol Cell Biol 24: 9079 –9091, 2004.
90. Irrcher I, Adhihetty PJ, Sheehan T, Joseph AM, Hood DA. PPAR␥
coactivator-1␣ expression during thyroid hormone- and contractile activity-induced mitochondrial adaptations. Am J Physiol Cell Physiol 284:
C1669 –C1677, 2003.
91. Irrcher I, Ljubicic V, Hood DA. Interactions between ROS and AMP
kinase activity in the regulation of PGC-1␣ transcription in skeletal
muscle cells. Am J Physiol Cell Physiol 296: C116 –C123, 2009.
92. Irrcher I, Ljubicic V, Kirwan AF, Hood DA. AMP-activated protein
kinase-regulated activation of the PGC-1alpha promoter in skeletal muscle cells. PLoS One 3: e3614, 2008.
93. Jäger S, Handschin C, St-Pierre J, Spiegelman BM. AMP-activated
protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc Natl Acad Sci USA 104: 12017–12022, 2007.
94. Jenkins AB, Storlein LH, Chisholm DJ, Kraegen EW. Effects of
nonesterified fatty acid availability on tissue-specific glucose utilization
in rats in vivo. J Clin Invest 82: 293–299, 1988.
95. Jenkins AB, Storlien LH, Cooney GJ, Denyer GS, Caterson ID,
Kraegen EW. Effects of blockade of fatty acid oxidation on whole body
and tissue-specific glucose metabolism in rats. Am J Physiol Endocrinol
Metab 265: E592–E600, 1993.
96. Jensen TE, Rose AJ, Jørgensen SB, Brandt N, Schjerling P,
Wojtaszewski JF, Richter EA. Possible CaMKK-dependent regulation
of AMPK phosphorylation and glucose uptake at the onset of mild tetanic
skeletal muscle contraction. Am J Physiol Endocrinol Metab 292:
E1308 –E1317, 2007.
97. Jiang LQ, Garcia-Roves PM, de Castro Barbosa T, Zierath JR.
Constitutively active calcineurin in skeletal muscle increases endurance
performance and mitochondrial respiratory capacity. Am J Physiol Endocrinol Metab 298: E8 –E16, 2010.
98. Jørgensen SB, Wojtaszewski JF, Viollet B, Andreelli F, Birk JB,
Hellsten Y, Schjerling P, Vaulont S, Neufer PD, Richter EA, Pilegaard H. Effects of alpha-AMPK knockout on exercise-induced gene
activation in mouse skeletal muscle. FASEB J 19: 1146 –1148, 2005.
99. Jové M, Salla J, Planavila A, Cabrero A, Michalik L, Wahli W,
Laguna JC, Vázquez-Carrera M. Impaired expression of NADH dehydrogenase subunit 1 and PPARgamma coactivator-1 in skeletal muscle
of ZDF rats: restoration by troglitazone. J Lipid Res 45: 113–123, 2004.
100. Kamei Y, Ohizumi H, Fujitani Y, Nemoto T, Tanaka T, Takahashi
N, Kawada T, Miyoshi M, Ezaki O, Kakizuka A. PPARgamma
coactivator 1beta/ERR ligand 1 is an ERR protein ligand, whose expression induces a high-energy expenditure and antagonizes obesity. Proc
Natl Acad Sci USA 100: 12378 –12383, 2003.
101. Kang C, O’Moore KM, Dickman JR, Ji LL. Exercise activation of
muscle peroxisome proliferator-activated receptor-gamma coactivator1alpha signaling is redox sensitive. Free Radic Biol Med 47: 1394 –1400,
2009.
102. Katz LD, Glickman MG, Rapoport S, Ferrannini E, DeFronzo RA.
Splanchnic and peripheral disposal of oral glucose in man. Diabetes 32:
675–679, 1983.
103. Kelley DE, He J, Menshikova EV, Ritov VB. Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 51:
2944 –2950, 2002.
104. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin
JM, Walker EA, Nathan DM. Reduction in the incidence of type 2
diabetes with lifestyle intervention or metformin. N Engl J Med 346:
393–403, 2002.
105. Koves TR, Li P, An J, Akimoto T, Slentz D, Ilkayeva O, Dohm GL,
Yan Z, Newgard CB, Muoio DM. Peroxisome proliferator-activated
receptor-gamma co-activator 1alpha-mediated metabolic remodeling of
skeletal myocytes mimics exercise training and reverses lipid-induced
mitochondrial inefficiency. J Biol Chem 280: 33588 –33598, 2005.
106. Koves TR, Ussher JR, Noland RC, Slentz D, Mosedale M, Ilkayeva
O, Bain J, Stevens R, Dyck JR, Newgard CB, Lopaschuk GD, Muoio
Review
PGC-1␣, EXERCISE TRAINING, AND INSULIN SENSITIVITY
AJP-Endocrinol Metab • VOL
143. Nesher R, Karl IE, Kipnis DM. Dissociation of effects of insulin and
contraction on glucose transport in rat epitrochlearis muscle. Am J
Physiol Cell Physiol 249: C226 –C232, 1985.
144. Nickerson JG, Alkhateeb H, Benton CR, Lally J, Nickerson J, Han
XX, Wilson MH, Jain SS, Snook LA, Glatz JF, Chabowski A, Luiken
JJ, Bonen A. Greater transport efficiencies of the membrane fatty acid
transporters FAT/CD36 and FATP4 compared with FABPpm and
FATP1 and differential effects on fatty acid esterification and oxidation
in rat skeletal muscle. J Biol Chem 284: 16522–16530, 2009.
145. Nisoli E, Falcone S, Tonello C, Cozzi V, Palomba L, Fiorani M,
Pisconti A, Brunelli S, Cardile A, Francolini M, Cantoni O, Carruba
MO, Moncada S, Clementi E. Mitochondrial biogenesis by NO yields
functionally active mitochondria in mammals. Proc Natl Acad Sci USA
101: 16507–16512, 2004.
146. Oliveira RL, Ueno M, de Souza CT, Pereira-da-Silva M, Gasparetti
AL, Bezzera RM, Alberici LC, Vercesi AE, Saad MJ, Velloso LA.
Cold-induced PGC-1␣ expression modulates muscle glucose uptake
through an insulin receptor/Akt-independent, AMPK-dependent pathway. Am J Physiol Endocrinol Metab 287: E686 –E695, 2004.
147. Pan DA, Lillioja S, Kriketos AD, Milner MR, Baur LA, Jenkins AB,
Storlien LH. Skeletal muscle triglyceride levels are inversely related to
insulin action. Diabetes 46: 983–988, 1997.
148. Patti ME, Butte AJ, Crunkhorn S, Cusi K, Berria R, Kashyap S,
Miyazaki Y, Kohane I, Costello M, Saccone R, Landaker EJ, Goldfine AB, Mun E, DeFronzo R, Finlayson J, Kahn CR, Mandarino LJ.
Coordinated reduction of genes of oxidative metabolism in humans with
insulin resistance and diabetes: Potential role of PGC1 and NRF1. Proc
Natl Acad Sci USA 100: 8466 –8471, 2003.
149. Pattwell DM, McArdle A, Morgan JE, Patridge TA, Jackson MJ.
Release of reactive oxygen and nitrogen species from contracting skeletal
muscle cells. Free Radic Biol Med 37: 1064 –1072, 2004.
150. Perdomo G, Commerford SR, Richard AM, Adams SH, Corkey BE,
O’Doherty RM, Brown NF. Increased beta-oxidation in muscle cells
enhances insulin-stimulated glucose metabolism and protects against
fatty acid-induced insulin resistance despite intramyocellular lipid accumulation. J Biol Chem 279: 27177–27186, 2004.
151. Perry CG, Heigenhauser GJ, Bonen A, Spriet LL. High-intensity
aerobic interval training increases fat and carbohydrate metabolic capacities in human skeletal muscle. Appl Physiol Nutr Metab 33: 1112–1123,
2008.
152. Petersen KF, Dufour S, Befroy D, Garcia R, Shulman GI. Impaired
mitochondrial activity in the insulin-resistant offspring of patients with
type 2 diabetes. N Engl J Med 350: 664 –671, 2004.
153. Pilegaard H, Saltin B, Neufer P. Exercise induces transient transcriptional activation of the PGC-1alpha gene in human skeletal muscle. J
Physiol 546: 851–858, 2003.
154. Pogozelski AR, Geng T, Li P, Yin X, Lira VA, Zhang M, Chi JT, Yan
Z. p38gamma mitogen-activated protein kinase is a key regulator in
skeletal muscle metabolic adaptation in mice. PLoS One 4: e7934, 2009.
155. Pratley RE, Thomson DB, Prochazka M, Baier L, Mott D, Ravussin
E, Sahkul H, Ehm MG, Burns DK, Foroud T, Garvey W, Hanson
RL, Knowler WC, Bennett PH, Bogardus C. An autosomal gneomic
scan for loci linked to pre-diabetic phenotypes in Pima Indians. J Clin
Invest 101: 1757–1764, 1998.
156. Prince FP, Hikida RS, Hagerman FC, Staron RS, Allen WH. A
morphometric analysis of human muscle fibers with relation to fiber types
and adaptations to exercise. J Neurol Sci 49: 165–179, 1981.
157. Puigserver P, Rhee J, Lin J, Wu Z, Yoon JC, Zhang CY, Krauss S,
Mootha VK, Lowell BB, Spiegelman BM. Cytokine stimulation of
energy expenditure through p38 MAP kinase activation of PPARgamma
coactivator-1. Mol Cell 8: 971–982, 2001.
158. Puigserver P, Spiegelman BM. Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): transcriptional coactivator and metabolic regulator. Endocr Rev 24: 78 –90, 2003.
159. Puigserver P, Wu Z, Park CW, Gracves R, Wright M, Spiegelman
BM. A cold-inducible coactivator of nuclear receptors linked to adaptive
thermogenesis. Cell 92: 829 –839, 1998.
160. Raney MA, Turcotte LP. Evidence for the involvement of CaMKII and
AMPK in Ca2⫹-dependent signaling pathways regulating FA uptake and
oxidation in contracting rodent muscle. J Appl Physiol 104: 1366 –1373,
2008.
161. Reid MB. Role of nitric oxide in skeletal muscle: synthesis, distribution
and functional importance. Acta Physiol Scand 162: 401–409, 1998.
299 • AUGUST 2010 •
www.ajpendo.org
Downloaded from ajpendo.physiology.org on February 26, 2011
125. Mathai AS, Bonen A, Benton CR, Robinson DL, Graham TE. Rapid
exercise-induced changes in PGC-1␣ mRNA and protein in human
skeletal muscle. J Appl Physiol 105: 1098 –1105, 2008.
126. McArdle A, Pattwell D, Vasilaki A, Griffiths RD, Jackson MJ.
Contractile activity-induced oxidative stress: cellular origin and adaptive
responses. Am J Physiol Cell Physiol 280: C621–C627, 2001.
127. McArdle F, Pattwell DM, Vasilaki A, McArdle A, Jackson MJ.
Intracellular generation of reactive oxygen species by contracting skeletal
muscle cells. Free Radic Biol Med 39: 651–657, 2005.
128. McConell GK, Ng GP, Phillips M, Ruan Z, Macaulay SL, Wadley
GD. Central role of nitric oxide synthase in AICAR and caffeine-induced
mitochondrial biogenesis in L6 myocytes. J Appl Physiol 108: 589 –595,
2010.
129. McCullagh KJ, Calabria E, Pallafacchina G, Ciciliot S, Serrano AL,
Argentini C, Kalhovde JM, Lomo T, Schiaffino S. NFAT is a nerve
activity sensor in skeletal muscle and controls activity-dependent myosin
switching. Proc Natl Acad Sci USA 101: 10590 –10595, 2004.
130. McGee SL, Fairlie E, Garnham AP, Hargreaves M. Exercise-induced
histone modifications in human skeletal muscle. J Physiol 587: 5951–
5958, 2009.
131. Meirhaeghe A, Crowley V, Lenaghan C, Lelliott C, Green K, Stewart
A, Hart K, Schinner S, Sethi JK, Yeo G, Brand MD, Cortright RN,
O’Rahilly S, Montague C, Vidal-Puig AJ. Characterization of the
human, mouse and rat PGC1 beta (peroxisome-proliferator-activated
receptor-gamma co-activator 1 beta) gene in vitro and in vivo. Biochem
J 373: 155–165, 2003.
132. Michael LF, Wu Z, Cheatham RB, Puigserver P, Adelmant G,
Lehman JJ, Kelly DP, Spiegelman BM. Restoration of insulin-sensitive
glucose transporter (GLUT4) gene expression in muscle cells by the
transcriptional coactivator PGC-1. Proc Natl Acad Sci USA 98: 3820 –
3825, 2001.
133. Miura S, Kai Y, Ono M, Ezaki O. Overexpression of peroxisome
proliferator-activated receptor gamma coactivator-1alpha down-regulates
GLUT4 mRNA in skeletal muscles. J Biol Chem 278: 31385–31390,
2003.
134. Miyazaki M, Hitomi Y, Kizaki T, Ohno H, Haga S, Takemasa T.
Contribution of the calcineurin signaling pathway to overload-induced
skeletal muscle fiber-type transition. J Physiol Pharmacol 55: 751–764,
2004.
135. Mogensen M, Sahlin K, Fernström M, Glintborg D, Vind BF, BeckNielsen H, Højlund K. Mitochondrial respiration is decreased in skeletal
muscle of patients with type 2 diabetes. Diabetes 56: 1592–1599, 2007.
136. Mootha VK, Handschin C, Arlow D, Xie X, St Pierre J, Sihag S,
Yang W, Altshuler D, Puigserver P, Patterson N, Willy PJ, Schulman
IG, Heyman RA, Lander ES, Spiegelman BM. Erralpha and Gabpa/b
specify PGC-1alpha-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle. Proc Natl Acad Sci USA 101:
6570 –6575, 2004.
137. Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S,
Lehar J, Puigserver P, Carlsson E, Ridderstrale M, Laurila E,
Houstis N, Daly MJ, Patterson N, Mesirov JP, Golub TR, Tamayo P,
Spiegelman B, Lander ES, Hirschhorn JN, Altshuler D, Groop LC.
PGC-1alpha-responsive genes involved in oxidative phosphorylation are
coordinately downregulated in human diabetes. Nat Genet 34: 267–273,
2003.
138. Morino K, Petersen KF, Shulman GI. Molecular mechanisms of
insulin resistance in humans and their potential links with mitochondrial
dysfunction. Diabetes 55, Suppl 2: S9 –S15, 2006.
139. Mortensen OH, Frandsen L, Schjerling P, Nishimura E, Grunnet N.
PGC-1␣ and PGC-1␤ have both similar and distinct effects on myofiber
switching toward an oxidative phenotype. Am J Physiol Endocrinol
Metab 291: E807–E816, 2006.
140. Mortensen OH, Plomgaard P, Fischer CP, Hansen AK, Pilegaard H,
Pedersen BK. PGC-1␤ is downregulated by training in human skeletal
muscle: no effect of training twice every second day vs. once daily on
expression of the PGC-1 family. J Appl Physiol 103: 1536 –1542, 2007.
141. Narkar VA, Downes M, Yu RT, Embler E, Wang YX, Banayo E,
Mihaylova MM, Nelson MC, Zou Y, Juguilon H, Kang H, Shaw RJ,
Evans RM. AMPK and PPARdelta agonists are exercise mimetics. Cell
134: 405–415, 2008.
142. Naya FJ, Mercer B, Shelton J, Richardson JA, Williams RS, Olson
EN. Stimulation of slow skeletal muscle fiber gene expression by
calcineurin in vivo. J Biol Chem 275: 4545–4548, 2000.
E159
Review
E160
PGC-1␣, EXERCISE TRAINING, AND INSULIN SENSITIVITY
AJP-Endocrinol Metab • VOL
183. Serrano AL, Murgia M, Pallafacchina G, Calabria E, Coniglio P,
Lomo T, Schiaffino S. Calcineurin controls nerve activity-dependent
specification of slow skeletal muscle fibers but not muscle growth. Proc
Natl Acad Sci USA 98: 13108 –13113, 2001.
184. Short KR, Vittone JL, Bigelow ML, Proctor DN, Rizza RA, CoenenSchimke JM, Nair KS. Impact of aerobic exercise training on agerelated changes in insulin sensitivity and muscle oxidative capacity.
Diabetes 52: 1888 –1896, 2003.
185. Silveira LR, Pereira-Da-Silva L, Juel C, Hellsten Y. Formation of
hydrogen peroxide and nitric oxide in rat skeletal muscle cells during
contractions. Free Radic Biol Med 35: 455–464, 2003.
186. Silveira LR, Pilegaard H, Kusuhara K, Curi R, Hellsten Y. The
contraction induced increase in gene expression of peroxisome proliferator-activated receptor (PPAR)-gamma coactivator 1alpha (PGC-1alpha),
mitochondrial uncoupling protein 3 (UCP3) and hexokinase II (HKII) in
primary rat skeletal muscle cells is dependent on reactive oxygen species.
Biochim Biophys Acta 1763: 969 –976, 2006.
187. Sjogaard G. Capillary supply and cross-sectional area of slow and fast
twitch muscle fibres in man. Histochemistry 76: 547–555, 1982.
188. Solomon TP, Sistrun SN, Krishnan RK, Del Aguila LF, Marchetti
CM, O’Carroll SM, O’Leary VB, Kirwan JP. Exercise and diet
enhance fat oxidation and reduce insulin resistance in older obese adults.
J Appl Physiol 104: 1313–1319, 2008.
189. Sriwijitkamol A, Ivy JL, Christ-Roberts C, Defronzo RA, Mandarino LJ, Musi N. LKB1-AMPK signaling in muscle from obese
insulin-resistant Zucker rats and effects of training. Am J Physiol Endocrinol Metab 290: E925–E932, 2006.
190. St-Pierre J, Lin J, Krauss S, Tarr PT, Yang R, Newgard CB,
Spiegelman BM. Bioenergetic analysis of peroxisome proliferator-activated receptor gamma coactivators 1alpha and 1beta (PGC-1alpha and
PGC-1beta) in muscle cells. J Biol Chem 278: 26597–26603, 2003.
191. Starritt EC, Howlett RA, Heigenhauser GJ, Spriet LL. Sensitivity of
CPT I to malonyl-CoA in trained and untrained human skeletal muscle.
Am J Physiol Endocrinol Metab 278: E462–E468, 2000.
192. Storlien LH, Jenkins AB, Chisholm DJ, Pascoe WS, Khouri S,
Kraegen EW. Influence of dietary fat composition on development of
insulin resistance in rats. Diabetes 40: 280 –289, 1991.
193. Stratford S, Hoehn KL, Liu F, Summers SA. Regulation of insulin
action by ceramide: dual mechanisms linking ceramide accumulation to
the inhibition of Akt/protein kinase B. J Biol Chem 279: 36608 –36615,
2004.
194. Summers SA, Garza LA, Zhou H, Birnbaum MJ. Regulation of
insulin-stimulated glucose transporter GLUT4 translocation and Akt
kinase activity by ceramide. Mol Cell Biol 18: 5457–5464, 1998.
195. Suwa M, Egashira T, Nakano H, Sasaki H, Kumagai S. Metformin
increases the PGC-1␣ protein and oxidative enzyme activities possibly
via AMPK phosphorylation in skeletal muscle in vivo. J Appl Physiol
101: 1685–1692, 2006.
196. Talanian JL, Galloway SD, Heigenhauser GJ, Bonen A, Spriet LL.
Two weeks of high-intensity aerobic interval training increases the
capacity for fat oxidation during exercise in women. J Appl Physiol 102:
1439 –1447, 2007.
197. Tatsumi R, Wuollet AL, Tabata K, Nishimura S, Tabata S, Mizunoya W, Ikeuchi Y, Allen RE. A role for calcium-calmodulin in
regulating nitric oxide production during skeletal muscle satellite cell
activation. Am J Physiol Cell Physiol 296: C922–C929, 2009.
198. Taylor EB, Lamb JD, Hurst RW, Chesser DG, Ellingson WJ, Greenwood LJ, Porter BB, Herway ST, Winder WW. Endurance training
increases skeletal muscle LKB1 and PGC-1␣ protein abundance: effects
of time and intensity. Am J Physiol Endocrinol Metab 289: E960 –E968,
2005.
199. Terada S, Goto M, Kawanaka K, Shimokawa T, Tabata I. Effects of
low-intensity prolonged exercise on PGC-1 mRNA expression in rat
epitrochlearis muscle. Biochem Biophys Res Commun 296: 350 –354,
2002.
200. Terada S, Tabata I. Effects of acute bouts of running and swimming
exercise on PGC-1␣ protein expression in rat epitrochlearis and soleus
muscle. Am J Physiol Endocrinol Metab 286: E208 –E216, 2004.
201. Termin A, Staron RS, Pette D. Myosin heavy chain isoforms in
histochemically defined fiber types of rat muscle. Histochemistry 92:
453–457, 1989.
202. Thomson DM, Herway ST, Fillmore N, Kim H, Brown JD, Barrow
JR, Winder WW. AMP-activated protein kinase phosphorylates tran-
299 • AUGUST 2010 •
www.ajpendo.org
Downloaded from ajpendo.physiology.org on February 26, 2011
162. Reid MB, Shoji T, Moody MR, Entman ML. Reactive oxygen in
skeletal muscle. II. Extracellular release of free radicals. J Appl Physiol
73: 1805–1809, 1992.
163. Reitman JS, Vasquez B, Klimes I, Nagulesparan M. Improvement of
glucose homeostasis after exercise training in non-insulin-dependent
diabetes. Diabetes Care 7: 434 –441, 1984.
164. Richardson DK, Kashyap S, Bajaj M, Cusi K, Mandarino SJ,
Finlayson J, Defronzo RA, Jenkinson CP, Mandarino LJ. Lipid
infusion decreases the expression of nuclear encoded mitochondrial
genes and increases the expression of extracellular matrix genes in
human skeletal muscle. J Biol Chem 280: 10290 –10297, 2005.
165. Ristow M, Zarse K, Oberbach A, Kloting N, Birringer M, Kiehntopf
M, Stumvoll M, Kahn CR, Bluher M. Antioxidants prevent healthpromoting effects of physical exercise in humans. Proc Natl Acad Sci
USA 106: 8665–8670, 2009.
166. Rivero JL, Talmadge RJ, Edgerton VR. Fibre size and metabolic
properties of myosin heavy chain-based fibre types in rat skeletal muscle.
J Muscle Res Cell Motil 19: 733–742, 1998.
167. Rivero JL, Talmadge RJ, Edgerton VR. Interrelationships of myofibrillar ATPase activity and metabolic properties of myosin heavy chainbased fibre types in rat skeletal muscle. Histochem Cell Biol 111:
277–287, 1999.
168. Rockl KS, Hirshman MF, Brandauer J, Fujii N, Witters LA, Goodyear LJ. Skeletal muscle adaptation to exercise training: AMP-activated
protein kinase mediates muscle fiber type shift. Diabetes 56: 2062–2069,
2007.
169. Rodríguez-Calvo R, Jové M, Coll T, Camins A, Sánchez RM, Alegret
M, Merlos M, Pallàs M, Laguna JC, Vázquez-Carrera M. PGC-1beta
down-regulation is associated with reduced ERRalpha activity and
MCAD expression in skeletal muscle of senescence-accelerated mice. J
Gerontol A Biol Sci Med Sci 61: 773–780, 2006.
170. Rose AJ, Hargreaves M. Exercise increases Ca2⫹-calmodulin-dependent protein kinase II activity in human skeletal muscle. J Physiol 553:
303–309, 2003.
171. Rose AJ, Kiens B, Richter EA. Ca2⫹-calmodulin-dependent protein
kinase expression and signalling in skeletal muscle during exercise. J
Physiol 574: 889 –903, 2006.
172. Russell AP, Feilchenfeldt J, Schreiber S, Praz M, Crettenand A,
Gobelet C, Meier CA, Bell DR, Kralli A, Giacobino JP, Deriaz O.
Endurance training in humans leads to fiber type-specific increases in
levels of peroxisome proliferator-activated receptor-gamma coactivator-1 and peroxisome proliferator-activated receptor-alpha in skeletal
muscle. Diabetes 52: 2874 –2881, 2003.
173. Russell AP, Hesselink MK, Lo SK, Schrauwen P. Regulation of
metabolic transcriptional co-activators and transcription factors with
acute exercise. FASEB J 19: 986 –988, 2005.
174. Ryder JW, Bassel-Duby R, Olson EN, Zierath JR. Skeletal muscle
reprogramming by activation of calcineurin improves insulin action on
metabolic pathways. J Biol Chem 278: 44298 –44304, 2003.
175. Rytinki MM, Palvimo JJ. SUMOylation modulates the transcription
repressor function of RIP140. J Biol Chem 283: 11586 –11595, 2008.
176. Sadana P, Zhang Y, Song S, Cook GA, Elam MB, Park EA. Regulation of carnitine palmitoyltransferase I (CPT-Ialpha) gene expression
by the peroxisome proliferator activated receptor gamma coactivator
(PGC-1) isoforms. Mol Cell Endocrinol 267: 6 –16, 2006.
177. Scarpulla RC. Transcriptional paradigms in mammalian mitochondrial
biogenesis and function. Physiol Rev 88: 611–638, 2008.
178. Schertzer JD, Plant DR, Lynch GS. Optimizing plasmid-based gene
transfer for investigating skeletal muscle structure and function. Mol
Ther 13: 795–803, 2006.
179. Schiaffino S, Sandri M, Murgia M. Activity-dependent signaling pathways controlling muscle diversity and plasticity. Physiology (Bethesda)
22: 269 –278, 2007.
180. Searle MS, Ready AE. Survey of exercise and dietary knowledge and
behaviour in persons with type II diabetes. Can J Public Health 82:
344 –348, 1991.
181. Segal KR, Edano A, Abalos A, Albu J, Blando L, Tomas MB,
Pi-Sunyer X. Effect of exercise training on insulin sensitivity and
glucose metabolism on lean, obese, and diabetic men. J Appl Physiol 71:
2402–2411, 1991.
182. Sellman JE, DeRuisseau KC, Betters JL, Lira VA, Soltow QA, Selsby
JT, Criswell DS. In vivo inhibition of nitric oxide synthase impairs
upregulation of contractile protein mRNA in overloaded plantaris muscle. J Appl Physiol 100: 258 –265, 2006.
Review
PGC-1␣, EXERCISE TRAINING, AND INSULIN SENSITIVITY
203.
204.
205.
206.
207.
209.
210.
211.
212.
213.
214.
215.
AJP-Endocrinol Metab • VOL
216. Widegren U, Jiang XJ, Krook A, Chibalin AV, Björnholm M, Tally
M, Roth RA, Henriksson J, Wallberg-henriksson H, Zierath JR.
Divergent effects of exercise on metabolic and mitogenic signaling
pathways in human skeletal muscle. FASEB J 12: 1379 –1389, 1998.
217. Winder WW, Hardie DG. Inactivation of acetyl-CoA carboxylase and
activation of AMP-activated protein kinase in muscle during exercise.
Am J Physiol Endocrinol Metab 270: E299 –E304, 1996.
218. Winder WW, Holmes BF, Rubink DS, Jensen EB, Chen M, Holloszy
JO. Activation of AMP-activated protein kinase increases mitochondrial
enzymes in skeletal muscle. J Appl Physiol 88: 2219 –2226, 2000.
219. Witzmann FA, Kim DH, Fitts RH. Hindlimb immobilization: lengthtension and contractile properties of skeletal muscle. J Appl Physiol 53:
335–345, 1982.
220. Wojtaszewski JF, Nielsen P, Hansen BF, Richter EA, Kiens B.
Isoform-specific and exercise intensity-dependent activation of 5=-AMPactivated protein kinase in human skeletal muscle. J Physiol 528: 221–
226, 2000.
221. Woods A, Dickerson K, Heath R, Hong SP, Momcilovic M, Johnstone SR, Carlson M, Carling D. Ca2⫹/calmodulin-dependent protein
kinase kinase-beta acts upstream of AMP-activated protein kinase in
mammalian cells. Cell Metab 2: 21–33, 2005.
222. Wright DC, Geiger PC, Han DH, Jones TE, Holloszy JO. Calcium
induces increases in peroxisome proliferator-activated receptor gamma
coactivator-1alpha and mitochondrial biogenesis by a pathway leading to
p38 mitogen-activated protein kinase activation. J Biol Chem 282:
18793–18799, 2007.
223. Wright DC, Han DH, Garcia-Roves PM, Geiger PC, Jones TE,
Holloszy JO. Exercise-induced mitochondrial biogenesis begins before
the increase in muscle PGC-1alpha expression. J Biol Chem 282: 194 –
199, 2007.
224. Wright DC, Hucker KA, Holloszy JO, Han DH. Ca2⫹ and AMPK both
mediate stimulation of glucose transport by muscle contractions. Diabetes 53: 330 –335, 2004.
225. Wu H, Kanatous SB, Thurmond FA, Gallardo T, Isotani E, BasselDuby R, Williams RS. Regulation of mitochondrial biogenesis in
skeletal muscle by CaMK. Science 296: 349 –352, 2002.
226. Wu H, Naya FJ, McKinsey TA, Mercer B, Shelton JM, Chin ER,
Simard AR, Michel RN, Bassel-Duby R, Olson EN, Williams RS.
MEF2 responds to multiple calcium-regulated signals in the control of
skeletal muscle fiber type. EMBO J 19: 1963–1973, 2000.
227. Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, Mootha V,
Troy A, Cinti S, Lowell B, Scarpulla RC, Spiegelman BM. Mechanisms controlling mitochondrial biogenesis and respiration through the
thermogenic coactivator PGC-1. Cell 98: 115–124, 1999.
228. Zhao M, New L, Kravchenko VV, Kato Y, Gram H, di Padova F,
Olson EN, Ulevitch RJ, Han J. Regulation of the MEF2 family of
transcription factors by p38. Mol Cell Biol 19: 21–30, 1999.
229. Zierath JR. Invited review: Exercise training-induced changes in insulin
signaling in skeletal muscle. J Appl Physiol 93: 773–781, 2002.
230. Zong H, Ren JM, Young LH, Pypaert M, Mu J, Birnbaum MJ,
Shulman GI. AMP kinase is required for mitochondrial biogenesis in
skeletal muscle in response to chronic energy deprivation. Proc Natl
Acad Sci USA 99: 15983–15987, 2002.
299 • AUGUST 2010 •
www.ajpendo.org
Downloaded from ajpendo.physiology.org on February 26, 2011
208.
scription factors of the CREB family. J Appl Physiol 104: 429 –438,
2008.
Thyfault JP, Cree MG, Zheng D, Zwetsloot JJ, Tapscott EB, Koves
TR, Ilkayeva O, Wolfe RR, Muoio DM, Dohm GL. Contraction of
insulin-resistant muscle normalizes insulin action in association with
increased mitochondrial activity and fatty acid catabolism. Am J Physiol
Cell Physiol 292: C729 –C739, 2007.
Timmons JA, Norrbom J, Scheele C, Thonberg H, Wahlestedt C,
Tesch P. Expression profiling following local muscle inactivity in
humans provides new perspective on diabetes-related genes. Genomics
87: 165–172, 2006.
Tomas E, Zorzano A, Ruderman NB. Exercise and insulin signaling: a
historical perspective. J Appl Physiol 93: 765–772, 2002.
Tsintzas K, Jewell K, Kamran M, Laithwaite D, Boonsong T, Littlewood J, Macdonald I, Bennett A. Differential regulation of metabolic
genes in skeletal muscle during starvation and refeeding in humans. J
Physiol 575: 291–303, 2006.
Turner N, Bruce CR, Beale SM, Hoehn KL, So T, Rolph MS, Cooney
GJ. Excess lipid availability increases mitochondrial fatty acid oxidative
capacity in muscle: evidence against a role for reduced fatty acid
oxidation in lipid-induced insulin resistance in rodents. Diabetes 56:
2085–2092, 2007.
van Loon LJ, Koopman R, Manders R, van der Weegen W, van
Kranenburg GP, Keizer HA. Intramyocellular lipid content in type 2
diabetes patients compared with overweight sedentary men and highly
trained endurance athletes. Am J Physiol Endocrinol Metab 287: E558 –
E565, 2004.
Vissing K, McGee SL, Roepstorff C, Schjerling P, Hargreaves M,
Kiens B. Effect of sex differences on human MEF2 regulation during
endurance exercise. Am J Physiol Endocrinol Metab 294: E408 –E415,
2008.
Wadley GD, Choate J, McConell GK. NOS isoform-specific regulation
of basal but not exercise-induced mitochondrial biogenesis in mouse
skeletal muscle. J Physiol 585: 253–262, 2007.
Wadley GD, McConell GK. Effect of nitric oxide synthase inhibition on
mitochondrial biogenesis in rat skeletal muscle. J Appl Physiol 102:
314 –320, 2007.
Wallberg-Henriksson H. Glucose transport into skeletal muscle. Influence of contractile activity, insulin, catecholamines and diabetes mellitus.
Acta Physiol Scand Suppl 564: 1–80, 1987.
Wareski P, Vaarmann A, Choubey V, Safiulina D, Liiv J, Kuum M,
Kaasik A. PGC-1{alpha} and PGC-1{beta} regulate mitochondrial density in neurons. J Biol Chem 284: 21379 –21385, 2009.
Watt MJ, Southgate RJ, Holmes AG, Febbraio MA. Suppression of
plasma free fatty acids upregulates peroxisome proliferator-activated
receptor (PPAR) alpha and delta and PPAR coactivator 1alpha in human
skeletal muscle, but not lipid regulatory genes. J Mol Endocrinol 33:
533–544, 2004.
Wende AR, Schaeffer PJ, Parker GJ, Zexhner C, Han DH, Chen M,
Hancock CR, Lehman JJ, Huss JM, McClain DA, Holloszy JO, Kelly
DP. A role for the transcriptional co-activator PGC-1␣ in muscle refuelling. J Biol Chem 282: 36642–36651, 2007.
E161