424
REVIEW / SYNTHÈSE
Exercise, PGC-1a, and metabolic adaptation in
skeletal muscle1
Zhen Yan
Abstract: Endurance exercise promotes skeletal muscle adaptation, and exercise-induced peroxisome proliferator-activated
receptor g coactivator-1a (Pgc-1a) gene expression may play a pivotal role in the adaptive processes. Recent applications
of mouse genetic models and in vivo imaging in exercise studies have started to delineate the signaling-transcription pathways that are involved in the regulation of the Pgc-1a gene. These studies revealed the importance of p38 mitogen-activated protein kinase/activating transcription factor 2 and protein kinase D/histone deacetylase 5 signaling transcription
axes in exercise-induced Pgc-1a transcription and metabolic adaptation in skeletal muscle. The signaling-transcription network that is responsible for exercise-induced skeletal muscle adaption remains to be fully elucidated.
Key words: exercise, skeletal muscle, fiber type transformation, angiogenesis, mitochondrial biogenesis, signal transduction,
transcription, p38 mitogen-activated protein kinase, peroxisome proliferator-activated receptor g coactivator-1a.
Résumé : L’exercice d’endurance suscite l’adaptation du muscle squelettique; l’expression du coactivateur-1a du récepteur
g activé de la prolifération des peroxysomes (« Pgc-1a ») pourrait jouer un rôle charnière dans ce processus adaptatif. Des
applications récentes des modèles de souris génétique et l’imagerie in vivo dans les études sur l’activité physique lèvent
un voile sur les mécanismes de transcription du signal dans la régulation du gène Pgc-1a. Ces études révèlent l’importance
de MAPK/ATF2 (protéine kinase activée par le mitogène p38 / facteur de transcription ATF2) et de PKD/HDAC5 (protéine kinase D/histone désacétylase 5) dans la transcription du Pgc-1a induite par l’exercice physique et l’adaptation métabolique du muscle squelettique. Le réseau de signalisation et de transcription responsable de l’adaptation du muscle
squelettique induite par l’exercice physique n’est pas encore bien délimité.
Mots-clés : exercice physique, muscle squelettique, transformation du myotype, angiogenèse, biogenèse mitochondriale,
transduction du signal, transcription, protéine kinase activée par le mitogène p38, coactivateur-1a du récepteur g activé de
la prolifération des peroxysomes.
[Traduit par la Rédaction]
Mammalian skeletal muscles are the source of power for
locomotion and other activities essential for survival. Loss
of contractile function is the major cause of falling, morbidity, and mortality, especially in elderly populations (Roubenoff 2000; Janssen et al. 2002). More important, skeletal
muscles participate in metabolism, the disruption of which
leads to and (or) exacerbates many chronic diseases, such
as coronary heart diseases, obesity, and type 2 diabetes
(Booth et al. 2002; Saltin and Pilegaard 2002). Regular exercise has significant positive impacts on most of these diseases, with no or few side effects. Improved understanding
of the molecular mechanisms of skeletal muscle adaptation
will not only provide information to guide the correct use
of regular exercise, but also facilitate new drug discovery to
combat the diseases.
Endurance exercise induces skeletal adaptation, which in-
cludes transformation of type IIb to IIa myofibers (referred
to as fiber-type transformation) (Fitzsimons et al. 1990), and
increased mitochondrial (Hoppeler et al. 1973; WallbergHenriksson et al. 1982) and capillary densities (referred to
as mitochondrial biogenesis and angiogenesis, respectively)
(Svedenhag et al. 1984), which are the fundamental basis
for the health benefits of regular exercise. It is believed
that an orchestrated signal transduction-transcription coupling from neuromuscular activity to the gene regulatory
machinery plays an essential role in the adaptation processes (Booth and Baldwin 1996; Williams and Neufer
1996; Sakamoto and Goodyear 2002). Adding to this complexity is a temporally cumulative induction of gene expression, which is required for the ultimate phenotypic
change (Williams and Neufer 1996).
Peroxisome proliferator activated receptor g coactivator
Received 25 February 2009. Accepted 25 February 2009. Published on the NRC Research Press Web site at apnm.nrc.ca on 5 May 2009.
Z. Yan. Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908, USA (e-mail:
zhen.yan@virginia.edu).
1This
paper article is one of a selection of papers published in this Special Issue, entitled 14th International Biochemistry of Exercise
Conference – Muscles as Molecular and Metabolic Machines, and has undergone the Journal’s usual peer review process.
Appl. Physiol. Nutr. Metab. 34: 424–427 (2009)
doi:10.1139/H09-030
Published by NRC Research Press
Yan
(PGC)-1a, a versatile transcription coactivator (Puigserver et
al. 1998), is involved in important cellular processes, such
as adaptive thermogenesis, fatty acid oxidation, gluconeogenesis, and mitochondrial biogenesis (Knutti and Kralli
2001). Numerous findings support the view that PGC-1a mediates and coordinates gene regulation during skeletal muscle
adaptation. First, Pgc-1a messenger (m)RNA and protein are
highly expressed in slow, oxidative fibers, compared with
fast, glycolytic fibers (Lin et al. 2002; Wu et al. 2002), consistent with the function of a gene involved in fiber-type specialization. Second, there is a tight correlation of muscle
contractile activity with increased Pgc-1a gene expression.
Endurance exercise induces Pgc-1a mRNA and protein expression in rats and humans (Goto et al. 2000; Baar et al.
2002; Terada et al. 2002; Irrcher et al. 2003; Pilegaard et al.
2003). Finally, Pgc-1a gene overexpression is sufficient to
enhance mitochondrial biogenesis and to promote fast-toslow fiber transformation in cultured myoblasts (Wu et al.
1999) and in transgenic mice (Lin et al. 2002), which leads
to improved exercise performance (Calvo et al. 2008).
Indeed, a global disruption of the Pgc-1a gene in mice resulted in a reduction of oxidative phenotype in skeletal
muscle (Arany et al. 2005; Leone et al. 2005; Handschin et
al. 2007). Surprisingly, Leick et al. (2008) recently showed,
in a global gene disruption mouse model, that lack of the
Pgc-1a gene does not prevent exercise-induced muscle
adaptive responses, despite a reduced basal level of expression of the genes that encode mitochondrial proteins. They
interpreted the findings to mean that PGC-1a is not mandatory for exercise-induced adaptive gene expression in skeletal muscle. However, results from my laboratory, using a
skeletal-muscle-specific gene targeting mouse model, suggest that Pgc-1a gene expression is required for exerciseinduced mitochondrial biogenesis and angiogenesis, but is
not required for fiber-type transformation (T. Akimoto,
Z. Yan 2009, unpublished results). These findings genetically segregate the metabolic adaptations from contractile
adaptation in skeletal muscle. The apparent differences between the 2 genetic models suggest the complexity of the
issue and justify a more vigorous delineation of the muscle
adaptation processes.
Multiple signaling transduction pathways are activated in
skeletal muscle during exercise, one of which involves calcium signaling decoding neuromuscular activity to gene
transcription for the adaptive processes. Calcineurin, a Ca2+/
calmodulin-dependent phosphatase, has been shown to play
a functional role in fiber transformation in both gain-offunction and loss-of-function animal models (Chin et al.
1998; Naya et al. 2000; Parsons et al. 2003); however, a direct involvement of calcineurin activity in exercise-induced
Pgc-1a gene regulation and enhanced mitochondrial biogenesis in skeletal muscle has not been established, as pharmacological inhibition of calcineurin failed to inhibit exerciseinduced Pgc-1a gene expression and enhanced mitochondrial biogenesis (Garcia-Roves et al. 2006). Some studies
have suggested that Ca2+/calmodulin-dependent protein kinase 4 plays an important role in skeletal muscle adaptation
(Wu et al. 2002; Zong et al. 2002), with a possible link to
the transcriptional control of the Pgc-1a gene (Handschin
et al. 2003), whereas more recent studies have ruled out
Ca2+/calmodulin-dependent protein kinase 4 as the endoge-
425
nous regulator of the Pgc-1a gene, since genetic disruption
of the gene did not prevent exercise-induced skeletal
muscle adaptation (Akimoto et al. 2004a). It remains to be
determined if other Ca2+/calmodulin-dependent protein kinase pathways play a role in the adaptive processes in skeletal muscle.
Endurance exercise training is associated with chronic
metabolic stress and energy deprivation. AMP-activated protein kinase (AMPK), a metabolic master switch in skeletal
muscle, can be activated in the muscles of exercised animals
and humans (Winder and Hardie 1996; Fujii et al. 2000;
Wojtaszewski et al. 2000). Pharmacological activation of
AMPK increases Pgc-1a gene expression and mitochondrial
biogenesis in skeletal muscle (Winder and Hardie 1996;
Zong et al. 2002; Suwa et al. 2006), and forced expression
of a dominant-negative form of AMPK in skeletal muscle
can block these adaptive processes (Zong et al. 2002). However, genetic disruption of functional AMPK isoforms failed
to block exercise-induced Pgc-1a gene expression and enhanced mitochondrial biogenesis in skeletal muscle (Jorgensen et al. 2005, 2006). The molecular link between
AMPK activity and Pgc-1a-mediated metabolic adaptation
in skeletal muscle remains to be fully investigated.
The mitogen-activated protein kinase (MAPK) signaling
molecules have also long been speculated to regulate gene
transcription in skeletal muscle in response to various
types of contractile activities. All 3 families of MAPK
pathways — extracellular signal-regulated kinase, c-Jun
NH(2)-terminal kinases, and p38 — can be activated by
increased contractile activity, and the p38 MAPK pathway
appears to play a direct role in Pgc-1a gene regulation
(Akimoto et al. 2005; Wright et al. 2007). Interestingly,
targeted disruption of the canonical upstream p38 MAPK
kinases, MAPK kinase 3 and MAPK kinase 6
(A.R. Pogozelski, T. Geng, P. Li, X. Yin, T. Akimoto,
V.A. Lira, M. Zhang, J.T. Chi, Z. Yan 2009, unpublished
results), occurs. Therefore, the upstream activator and the
p38 isoform(s) that are required for exercise-training-induced
Pgc-1a gene transcription and enhanced mitochondrial biogenesis remain to be identified.
Finally, to investigate the transcriptional control of the
Pgc-1a gene in skeletal muscle in vivo, my laboratory has
established a bioluminescence-based optical imaging system
to analyze promoter activity in live animals. This unique in
vivo imaging system, in combination with electric pulsemediated gene transfer, allows us to measure the Pgc-1a
gene activity in skeletal muscle in live mice. We have
shown that contractile activity-induced Pgc-1a gene transcription in skeletal muscle depends on both the myocyte
enhancer factor 2 (MEF2) binding sites and the cyclic-AMP
responsive element consensus sequence on the Pgc-1a promoter (Akimoto et al. 2004b). Expanding this unique system
by in vivo cotransfection of the Pgc-1a-luciferase reporter
gene with genes encoding dominant negative forms of potential upstream regulatory factors, we have confirmed the
essential role of activating transcription factor 2 (binding to
the cyclic-AMP responsive element site) and histone deacetylase 5 (repressing MEF2 function), but not histone deacetylase 4, to contractile activity-induced Pgc-1a
transcription (Akimoto et al. 2008). These findings provide
in vivo information about Pgc-1a transcriptional regulation
Published by NRC Research Press
426
in response to increased contractile activity in skeletal
muscle. Future studies should define the causal relationships
of the upstream signaling pathways to the Pgc-1a gene that
are responsible for neuromuscular activity-mediated skeletal
muscle adaptation.
In summary, new findings support the pivotal role that
Pgc-1a gene expression plays in metabolic, but not contractile, adaptation in skeletal muscle adaptation. p38 MAPK/
activating transcription factor 2 and kinase D/histone deacetylase5/MEF2 signaling transcription axes mediate exerciseinduced Pgc-1a transcription and metabolic adaptation in
skeletal muscle. The signaling-transcription network responsible for exercise-induced skeletal muscle adaption remains to be fully elucidated.
Acknowledgements
This work was supported by National Institutes of Health
Grant AR050429 (to Z.Y.).
References
Akimoto, T., Ribar, T.J., Williams, R.S., and Yan, Z. 2004a. 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. doi:10.1152/ajpcell.
00248.2004. PMID:15229108.
Akimoto, T., Sorg, B.S., and Yan, Z. 2004b. Real-time imaging of
peroxisome proliferator-activated receptor-g coactivator-1a promoter activity in skeletal muscles of living mice. Am. J. Physiol.
Cell Physiol. 287: C790–C796. doi:10.1152/ajpcell.00425.2003.
PMID:15151904.
Akimoto, T., Pohnert, S.C., Li, P., Zhang, M., Gumbs, C.,
Rosenberg, P.B., et al. 2005. Exercise stimulates Pgc-1a transcription in skeletal muscle through activation of the p38
MAPK pathway. J. Biol. Chem. 280: 19587–19593. doi:10.
1074/jbc.M408862200. PMID:15767263.
Akimoto, T., Li, P., and Yan, Z. 2008. Functional interaction of
regulatory factors with the Pgc-1a promoter in response to exercise by in vivo imaging. Am. J. Physiol. 295: C288–C292.
doi:10.1152/ajpcell.00104.2008. PMID:18434626.
Arany, Z., He, H., Lin, J., Hoyer, K., Handschin, C., Toka, O., et al.
2005. Transcriptional coactivator PGC-1a controls the energy
state and contractile function of cardiac muscle. Cell Metab. 1:
259–271. doi:10.1016/j.cmet.2005.03.002. PMID:16054070.
Baar, K., Wende, A.R., Jones, T.E., Marison, M., Nolte, L.A.,
Chen, M., et al. 2002. Adaptations of skeletal muscle to exercise: rapid increase in the transcriptional coactivator PGC-1.
FASEB J. 16: 1879–1886. doi:10.1096/fj.02-0367com. PMID:
12468452.
Booth, F.W., and Baldwin, K.M. 1996. Muscle plasticity: energy
demand and supply processes. In The handbook of physiology.
Exercise: regulation and integration of multiple systems. Edited
by L.B. Rowell and J.T. Shepherd. Oxford University Press,
New York. pp. 1075–1123.
Booth, F.W., Chakravarthy, M.V., Gordon, S.E., and Spangenburg,
E.E. 2002. Waging war on physical inactivity: using modern
molecular ammunition against an ancient enemy. J. Appl. Physiol. 93: 3–30. PMID:12070181.
Calvo, J.A., Daniels, T.G., Wang, X., Paul, A., Lin, J., Spiegelman,
B.M., et al. 2008. Muscle-specific expression of PPARg coactivator-1a improves exercise performance and increases peak oxygen uptake. J. Appl. Physiol. 104: 1304–1312. doi:10.1152/
japplphysiol.01231.2007. PMID:18239076.
Appl. Physiol. Nutr. Metab. Vol. 34, 2009
Chin, E.R., Olson, E.N., Richardson, J.A., Yang, Q., Humphries,
C., Shelton, J.M., et al. 1998. A calcineurin-dependent transcriptional pathway controls skeletal muscle fiber type. Genes Dev.
12: 2499–2509. doi:10.1101/gad.12.16.2499. PMID:9716403.
Fitzsimons, D.P., Diffee, G.M., Herrick, R.E., and Baldwin, K.M.
1990. Effects of endurance exercise on isomyosin patterns in
fast- and slow-twitch skeletal muscles. J. Appl. Physiol. 68:
1950–1955. PMID:2141832.
Fujii, N., Hayashi, T., Hirshman, M.F., Smith, J.T., Habinowski,
S.A., Kaijser, L., et al. 2000. Exercise induces isoform-specific
increase in 5’AMP-activated protein kinase activity in human
skeletal muscle. Biochem. Biophys. Res. Commun. 273: 1150–
1155. doi:10.1006/bbrc.2000.3073. PMID:10891387.
Garcia-Roves, P.M., Huss, J., and Holloszy, J.O. 2006. Role of calcineurin in exercise-induced mitochondrial biogenesis. Am. J.
Physiol. Endocrinol. Metab. 290: E1172–E1179. doi:10.1152/
ajpendo.00633.2005. PMID:16403773.
Goto, M., Terada, S., Kato, M., Katoh, M., Yokozeki, T., Tabata,
I., and Shimokawa, T. 2000. cDNA Cloning and mRNA analysis
of PGC-1 in epitrochlearis muscle in swimming-exercised rats.
Biochem. Biophys. Res. Commun. 274: 350–354. doi:10.1006/
bbrc.2000.3134. PMID:10913342.
Handschin, C., Rhee, J., Lin, J., Tarr, P.T., and Spiegelman, B.M.
2003. An autoregulatory loop controls peroxisome proliferatoractivated receptor g coactivator 1a expression in muscle. Proc.
Natl. Acad. Sci. U.S.A. 100: 7111–7116. doi:10.1073/pnas.
1232352100. PMID:12764228.
Handschin, C., Chin, S., Li, P., Liu, F., Maratos-Flier, E., Lebrasseur,
N.K., et al. 2007. Skeletal muscle fiber-type switching, exercise
intolerance, and myopathy in PGC-1a muscle-specific knock-out
animals. J. Biol. Chem. 282: 30014–30021. doi:10.1074/jbc.
M704817200. PMID:17702743.
Hoppeler, H., Luthi, P., Claassen, H., Weibel, E.R., and Howald,
H. 1973. The ultrastructure of the normal human skeletal muscle. A morphometric analysis on untrained men, women and
well-trained orienteers. Pflugers Arch. 344: 217–232. doi:10.
1007/BF00588462. PMID:4797912.
Irrcher, I., Adhihetty, P.J., Sheehan, T., Joseph, A.M., and Hood, D.A.
2003. PPARg coactivator-1a expression during thyroid hormoneand contractile activity-induced mitochondrial adaptations. Am. J.
Physiol. Cell Physiol. 284: C1669–C1677. PMID:12734114.
Janssen, I., Heymsfield, S.B., and Ross, R. 2002. Low relative skeletal muscle mass (sarcopenia) in older persons is associated
with functional impairment and physical disability. J. Am. Geriatr. Soc. 50: 889–896. doi:10.1046/j.1532-5415.2002.50216.x.
PMID:12028177.
Jorgensen, S.B., Wojtaszewski, J.F., Viollet, B., Andreelli, F., Birk,
J.B., Hellsten, Y., et al. 2005. Effects of alpha-AMPK knockout
on exercise-induced gene activation in mouse skeletal muscle.
FASEB J. 19: 1146–1148. PMID:15878932.
Jorgensen, S.B., Richter, E.A., and Wojtaszewski, J.F. 2006. Role
of AMPK in skeletal muscle metabolic regulation and adaptation
in relation to exercise. J. Physiol. 574: 17–31. doi:10.1113/
jphysiol.2006.109942. PMID:16690705.
Knutti, D., and Kralli, A. 2001. PGC-1, a versatile coactivator.
Trends Endocrinol. Metab. 12: 360–365. doi:10.1016/S10432760(01)00457-X. PMID:11551810.
Leick, L., Wojtaszewski, J.F., Johansen, S.T., Kiilerich, K., Comes,
G., Hellsten, Y., et al. 2008. PGC-1a is not mandatory for exercise- and training-induced adaptive gene responses in mouse
skeletal muscle. Am. J. Cell Physiol. 294: E463–E474.
PMID:18073319.
Leone, T.C., Lehman, J.J., Finck, B.N., Schaeffer, P.J., Wende,
A.R., Boudina, S., et al. 2005. PGC-1a deficiency causes multiPublished by NRC Research Press
Yan
system energy metabolic derangements: muscle dysfunction, abnormal weight control and hepatic steatosis. PLoS Biol. 3: e101.
doi:10.1371/journal.pbio.0030101. PMID:15760270.
Lin, J., Wu, H., Tarr, P.T., Zhang, C.Y., Wu, Z., Boss, O., et al.
2002. Transcriptional co-activator PGC-1a drives the formation
of slow-twitch muscle fibres. Nature, 418: 797–801. doi:10.
1038/nature00904. PMID:12181572.
Naya, F.J., Mercer, B., Shelton, J., Richardson, J.A., Williams,
R.S., and Olson, E.N. 2000. Stimulation of slow skeletal muscle
fiber gene expression by calcineurin in vivo. J. Biol. Chem. 275:
4545–4548. doi:10.1074/jbc.275.7.4545. PMID:10671477.
Parsons, S.A., Wilkins, B.J., Bueno, O.F., and Molkentin, J.D.
2003. Altered skeletal muscle phenotypes in calcineurin Aa and
Ab gene-targeted mice. Mol. Cell. Biol. 23: 4331–4343. doi:10.
1128/MCB.23.12.4331-4343.2003. PMID:12773574.
Pilegaard, H., Saltin, B., and Neufer, P.D. 2003. Exercise induces
transient transcriptional activation of the PGC-1a gene in human
skeletal muscle. J. Physiol. 546: 851–858. doi:10.1113/jphysiol.
2002.034850. PMID:12563009.
Puigserver, P., Wu, Z., Park, C.W., Graves, R., Wright, M., and
Spiegelman, B.M. 1998. A cold-inducible coactivator of nuclear
receptors linked to adaptive thermogenesis. Cell, 92: 829–839.
doi:10.1016/S0092-8674(00)81410-5. PMID:9529258.
Roubenoff, R. 2000. Sarcopenia and its implications for the elderly.
Eur. J. Clin. Nutr. 54(Suppl. 3): S40–S47. PMID:11041074.
Sakamoto, K., and Goodyear, L.J. 2002. Invited review: intracellular signaling in contracting skeletal muscle. J. Appl. Physiol. 93:
369–383. PMID:12070227.
Saltin, B., and Pilegaard, H. 2002. Metabolic fitness: physical activity and health. Ugeskr. Laeger, 164: 2156–2162. PMID:
11989061.
Suwa, M., Egashira, T., Nakano, H., Sasaki, H., and Kumagai, S.
2006. Metformin increases the PGC-1a protein and oxidative
enzyme activities possibly via AMPK phosphorylation in skeletal muscle in vivo. J. Appl. Physiol. 101: 1685–1692. doi:10.
1152/japplphysiol.00255.2006. PMID:16902066.
Svedenhag, J., Henriksson, J., and Juhlin-Dannfelt, A. 1984. Betaadrenergic blockade and training in human subjects: effects on
muscle metabolic capacity. Am. J. Physiol. 247: E305–E311.
PMID:6089581.
Terada, S., Goto, M., Kato, M., Kawanaka, K., Shimokawa, T., and
Tabata, I. 2002. Effects of low-intensity prolonged exercise on
427
PGC-1 mRNA expression in rat epitrochlearis muscle. Biochem.
Biophys. Res. Commun. 296: 350–354. doi:10.1016/S0006291X(02)00881-1. PMID:12163024.
Wallberg-Henriksson, H., Gunnarsson, R., Henriksson, J., DeFronzo,
R., Felig, P., Ostman, J., and Wahren, J. 1982. Increased peripheral insulin sensitivity and muscle mitochondrial enzymes but unchanged blood glucose control in type I diabetics after physical
training. Diabetes, 31: 1044–1050. doi:10.2337/diabetes.31.12.
1044. PMID:6757018.
Williams, R.S., and Neufer, P.D. 1996. Regulation of gene expression in skeletal muscle by contractile activity. In The handbook
of physiology. Exercise: regulation and integration of multiple
systems. Edited by L.B.Rowell and J.T. Shepherd. Oxford University Press, New York. pp. 1124–1150.
Winder, W.W., and Hardie, D.G. 1996. Inactivation of acetyl-CoA
carboxylase and activation of AMP-activated protein kinase in
muscle during exercise. Am. J. Physiol. 270: E299–E304.
PMID:8779952.
Wojtaszewski, J.F., Nielsen, P., Hansen, B.F., Richter, E.A., and
Kiens, B. 2000. Isoform-specific and exercise intensity-dependent
activation of 5’-AMP-activated protein kinase in human skeletal
muscle. J. Physiol. 528: 221–226. doi:10.1111/j.1469-7793.2000.
t01-1-00221.x. PMID:11018120.
Wright, D.C., Han, D.H., Garcia-Roves, P.M., Geiger, P.C., Jones,
T.E., and Holloszy, J.O. 2007. Exercise-induced mitochondrial
biogenesis begins before the increase in muscle PGC-1a expression. J. Biol. Chem. 282: 194–199. doi:10.1074/jbc.M606116200.
PMID:17099248.
Wu, H., Kanatous, S.B., Thurmond, F.A., Gallardo, T., Isotani, E.,
Bassel-Duby, R., and Williams, R.S. 2002. Regulation of mitochondrial biogenesis in skeletal muscle by CaMK. Science, 296:
349–352. doi:10.1126/science.1071163. PMID:11951046.
Wu, Z., Puigserver, P., Andersson, U., Zhang, C., Adelmant, G.,
Mootha, V., et al. 1999. Mechanisms controlling mitochondrial
biogenesis and respiration through the thermogenic coactivator
PGC-1. Cell, 98: 115–124. doi:10.1016/S0092-8674(00)80611X. PMID:10412986.
Zong, H., Ren, J.M., Young, L.H., Pypaert, M., Mu, J., Birnbaum,
M.J., and Shulman, G.I. 2002. AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic
energy deprivation. Proc. Natl. Acad. Sci. U.S.A. 99: 15983–
15987. doi:10.1073/pnas.252625599. PMID:12444247.
Published by NRC Research Press