Bio Chem Ch 47
Muscle Cell Types
 Skeletal muscles – attached to bone and facilitate movement of skeleton; found in pairs, which are responsible
for opposing, coordinated directions of motion on skeleton
o Muscle cells – long, cylindrical fibers that run length of muscle; fibers multinucleated because of cell
fusion during embryogenesis
o PM surrounding fibers is sarcolemma
o Sarcoplasmic reticulum – analogous to endoplasmic reticulum in other cell types and is an internal
membrane system that runs throughout length of muscle fiber
o Transverse tubules (T tubules) – thousands of invaginations of sarcolemma that tunnel from surface
toward center of muscle fiber to make contact with terminal cisterns of sarcoplasmic reticulum
 T tubules open to outside of muscle fiber and filled with extracellular fluid, so muscle AP that
propagates along surface of muscle fiber’s sarcolemma travels into T tubules to SR
o Myofibrils – thread-like structures consisting of thin and thick filaments; organization gives muscle
striations; actin and myosin contained in the filaments (myosin in thick filaments and actin in thin
filaments); sliding of filaments relative to each other, using myosin-catalyzed ATP hydrolysis as energy
source, allows for contraction and relaxation of muscle
o Damaged muscle cells release myoglobin, which can be observed clinically as reddish tint to urine
 Primary measurement for myoglobin via immunoassays – primary antibody linked to insoluble
support; second antibody linked to ALK
 If myoglobin high in sera, it could be sign of MI
 If myoglobin high in urine, muscle damage and potential renal failure could be culprits
o Duchenne muscular dystrophy caused by absence of dystrophin (structural protein located in
sarcolemma); dystrophin required to maintain integrity of sarcolemma and when absent, there is loss of
muscle function, caused by breakdown of sarcolemma
 Gene is X-linked; generally results from large deletions of gene, so dystrophin completely gone
 Becker muscular dystrophy – caused by point mutations in dystrophin gene; dystrophin present
in sarcolemma, but in mutated form
o Type I fibers – slow-twitch fibers; slow-oxidative fibers; contain large amounts of mitochondria and
myoglobin (red), use respiration and oxidative phosphorylation for energy, relatively resistant to fatigue
 Low glycogen content
 Develop force slowly but maintain contractions longer
o Type II fibers – fast-twitch fibers
 Type IIa – fast-oxidative glycolytic fibers; have properties of both type I and IIb fibers
 Intermediate-twich; intermediate glycogen levels; intermediate fiber diameter
 High myoglobin content (appear red); increased oxidative capacity on training
 Intermediate resistance to fatigue
 Type IIb – fast-glycolytic fibers; few mitochondria and low levels of myoglobin (appear white)
 Rich in glycogen and use glycogenolysis and glycolysis as primary energy source
 Prone to fatigue because continued reliance on glycolysis to produce ATP leads to
increase in lactic acid levels, resulting in drop in intracellular pH, causing ability of
muscle to produce ATP to diminish
 Can develop greater force than type I fibers, so contractions occur more rapidly
o Muscles are mixture of different fiber types, but depending on function, muscle may have
preponderance of one fiber type over another
 Type I fibers found in postural muscles such as psoas or soleus
 Triceps has only 32.6% type I
 Type II fibers more prevalent in large muscles of limbs responsible for sudden, powerful
movements; more type II in extraocular muscles
 Smooth muscle cells – found in digestive system, blood vessels, bladder, airways, and uterus
o Cells have spindle shape with central nucleus
o Cells have ability to maintain tension for extended periods, and do so efficiently, with low use of energy
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Cardiac muscle cells – cells are quadrangular in shape and form network with multiple other cells through tight
membrane junctions and gap junctions
o Multicellular contacts allow cells to act as common unit and to contract and relax synchronously
o Depend on aerobic metabolism for energy needs because they contain many mitochondria and very
little glycogen; generate small amount of energy from glycolysis using glucose derived from glycogen
o Amount of ATP that can be generated by glycolysis alone not sufficient to meet energy requirements of
contracting heart (hence why losing blood supply is bad so fast)
Neuronal Signals to Muscle
 Ryanodine receptors – calcium release channels found in ER and SR of muscle cells
o One type of receptor activated by depolarization signal (depolarization-induced calcium release)
o Another receptor type activated by calcium ions (calcium-induced calcium release)
o Ryanodine inhibits SR calcium release and acts as paralytic agent; first used in insecticides
 Acetylcholine levels in neuromuscular junction rapidly reduced by enzyme acetylcholinesterase
o Number of nerve gas poisons act to inhibit acetylcholinesterase (such as sarin and VX) so that muscles
continuously stimulated to contract
o Leads top blurred vision, bronchoconstriction, seizures, respiratory arrest, and death
o Poisons are covalent modifiers of acetylcholinesterase; therefore, recovery from exposure to such
poisons requires synthesis of new enzyme
o New generation of acetylcholinesterase inhibitors, which act reversibly, being used to treat dementia
(especially dementia brought about by Alzheimer disease)
 When appropriately stimulated, nerve cell releases acetylcholine at junction, which binds to acetylcholine
receptors on muscle membrane; binding stimulates opening of sodium channels on sarcolemma
o Massive influx of sodium ions results in generation of AP in sarcolemma at edges of motor end plate of
neuromuscular junction
o AP sweeps across surface of muscle fiber and down T tubules to SR, where it initiates release of calcium
from its lumen via ryanodine receptor
o Ca2+ binds to troponin, resulting in conformational change in troponin-tropomyosin complexes so they
move away from myosin-binding sites on actin
o As long as Ca2+ and ATP remain available, myosin heads will repeat cycle of attachment, pivoting, and
detachment; movement requires ATP, and when ATP levels low (i.e., ischemia), ability of muscle to relax
or contract compromised
o As calcium release channel closes, Ca2+ pumped back into SR against concentration gradient using
energy-requiring protein SERCA and contraction stops
Glycolysis and Fatty Acid Metabolism in Muscle Cells
 PFK-2 – negatively regulated by phosphorylation in liver (enzyme that catalyzes phosphorylation is cAMPdependent protein kinase); in skeletal muscle, PFK-2 not regulated by phosphorylation because skeletal muscle
isozyme of PFK-2 lacks regulatory serine residue, which is phosphorylated in liver
o Cardiac isozyme of PFK-2 phosphorylated and activated by kinase cascade initiated by insulin, allowing
heart to activate glycolysis and use blood glucose when blood glucose levels elevated
o AMP-activated protein kinase also activates cardiac PFK-2 (kinase activity) as signal that energy low
 Fatty acid uptake by muscle requires participation of fatty acid-binding proteins and usual enzymes of fatty acid
oxidation
 Fatty acyl-CoA uptake into mitochondria controlled by malonyl-CoA, which is produced by an isozyme of acetylCoA carboxylase (ACC-2; ACC-1 isozyme found in liver and adipose tissue cytosol and used for fatty acid
biosynthesis)
o ACC-2 (mitochondrial protein, linked to CPTI in outer mitochondrial membrane) inhibited by
phosphorylation by AMP-activated protein kinase (AMP-PK) so that when energy levels low, levels of
malonyl-CoA drop, allowing fatty acid oxidation by mitochondria
o Muscle cells contain malonyl-CoA decarboxylase, which is activated by phosphorylation by AMP-PK
o Malonyl-CoA decarboxylase converts malonyl-CoA to acetyl-CoA, relieving inhibition of CPTI and
stimulating fatty acid oxidation
o Muscle cells do not synthesize fatty acids; presence of acetyl-CoA carboxylase in muscle exclusively for
regulatory purposes
o
Those that lack ACC-2 have 50% reduction of fat stores because of 30% increase in skeletal muscle fatty
acid oxidation resulting from dysregulation of CPTI, brought about by lack of malonyl-CoA inhibition of
CPTI
Fuel Use in Cardiac Muscle
 Normally, heart uses primarily fatty acids (60-80%), lactate, and glucose (20-40%) as energy sources
 98% of cardiac ATP generated by oxidative means, and 2% derived from glycolysis
o Lactate used by heart taken up by monocarboxylate transporter in PM that is also used for transport of
ketone bodies
o Ketone bodies not preferred fuel for heart; heart prefers to use fatty acids
 Lactate generated by RBCs and working skeletal muscle; when lactate used by heart, it is oxidized to CO2 and
H2O, following pathway lactate to pyruvate, pyruvate to acetyl-CoA, acetyl-CoA oxidation in TCA cycle, and ATP
synthesis through oxidative phosphorylation
o Alternative fate for lactate is use in reactions of Cori cycle in liver
 Glucose transport into cardiocyte occurs via both GLUT1 and GLUT4 transporters, although 90% of transporters
are GLUT4
o Insulin stimulates increase in number of GLUT4 transporters in cardiac PM, as does myocardial ischemia
o Ischemia-induced increase in GLUT4 transporter number additive to effect of insulin on translocation of
GLUT4 transporters to PM
 Fatty acid uptake into cardiac muscle similar to that for other muscle cell types and requires fatty acid-binding
proteins and carnitine palmitoyl transferase I for transfer into mitochondria
o Fatty acid oxidation in cardiac muscle cells regulated by altering activities of ACC-2 and malonyl-CoA
decarboxylase
o Under conditions in which ketone bodies produced, fatty acid levels in plasma also elevated
o Because heart preferentially burns fatty acids as fuel rather than ketone bodies produced by liver,
ketone bodies spared for use by nervous system
 New class of drugs (partial fatty acid oxidation or pFOX inhibitors) developed to reduce extensive fatty acid
oxidation in heart after ischemic episode
o Reduction in fatty acid oxidation induced by drug allows glucose oxidation to occur and reduce lactate
buildup in damaged heart muscle
o Other possible targets include ACC-2, malonyl-CoA decarboxylase, and carnitine palmitoyl transferase I
 When blood flow to heart interrupted, heart switches to anaerobic metabolism
o Rate of glycolysis increases, but accumulation of protons (via lactate formation) detrimental to heart
o Ischemia increases levels of free fatty acids in blood and, when oxygen reintroduced to heart, high rate
of fatty acid oxidation in heart detrimental to recovery of damaged heart cells
 Fatty acid oxidation occurs so rapidly that NADH accumulates in mitochondria, leading to
reduced rate of NADH shuttle activity, increased cytoplasmic NADH level, and lactate formation,
which generates more protons
o Fatty acid oxidation increases levels of mitochondrial acetyl-CoA, which inhibits pyruvate
dehydrogenase, leading to cytoplasmic pyruvate accumulation and lactate production; as lactate
production increases and intracellular pH of heart drops, it is more difficult to maintain ion gradients
across sarcolemma, and ATP hydrolysis necessarily to repair gradients essential for heart function
o Use of ATP for gradient repair reduces amount of ATP available for heart to use in contraction, which, in
turn, compromises ability of heart to recover from ischemic event
Fuel Use in Skeletal Muscle
 Most abundant immediate source of ATP is creatine phosphate
 ATP can be generated from glycogen stores, either anaerobically (generating lactate) or aerobically, in which
case pyruvate converted to acetyl-CoA for oxidation via TCA cycle
 All human skeletal muscles have some mitochondria and thus are capable of fatty acid and ketone body
oxidation
 Skeletal muscles capable of completely oxidizing carbon skeletons of alanine, aspartate, glutamate, valine,
leucine, and isoleucine, but not other amino acids
 ATP not good choice to store in quantity for energy reserves; many reactions allosterically activated or inhibited
by ATP levels, especially those that generate energy
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Muscle cells store high-energy phosphate bonds in form of creatine phosphate; when energy required,
creatine phosphate donates phosphate to ADP to regenerate ATP for muscle contraction
o Creatine synthesis begins in kidney and is completed in liver
 In kidney, glycine combines with arginine to form guanidinoacetate; guanidinium group of
arginine (group that also forms urea) transferred to glycine, and remainder of arginine molecule
released as ornithine
 Guanidinoacetate travels to liver, where it is methylated by S-adenosylmethionine to form
creatine, which is released from liver and travels through bloodstream to other tissues,
particularly brain, heart, and skeletal muscle, where it reacts with ATP to form high-energy
compound creatine phosphate
 Conversion to creatine phosphate catalyzed by creatine phosphokinase (CK) and is reversible
o CK is unstable compound that spontaneously cyclizes, forming creatinine, which cannot be further
metabolized and is excreted in urine
 Amount of creatinine excreted each day is constant and depends on body muscle mass
 Can be used as gauge of determining amounts of other compounds excreted in urine and as
indicator of renal excretory function
 Daily volume of urine determined by factors such as volume of blood reaching renal glomeruli
and amount of renal tubular fluid reabsorbed from tubular urine back into interstitial space of
kidneys over time
 At any given moment, concentration of compound in single urine specimen doesn’t give good
indication of total amount being excreted on daily basis, but if concentration of that compound
divided by concentration of creatinine, result provides better indication of true excretion rate
o Metabolites such as creatinine leave blood by passing through pores or channels in glomerlular
capillaries and enter fluid within proximal kidney tubule for eventual excretion in urine
 When functionally intact, glomerular tissues impermeable to all but smallest proteins
 When acutely inflamed, barrier function lost to varying degrees, and albumin and other proteins
may appear in urine
 Marked inflammatory changes in glomerular capillaries that accompany post-streptococcal
glomerulonephritis significantly reduce flow of blood to filtering surfaces of vessels; as result,
creatinine, urea, and other circulating metabolites that are filtered into urine at normal rate
(GFR) in absence of kidney disease fail to reach filters, and therefore, they accumulate in plasma
 In most patients, prognosis is excellent, although in some patients, recovery may not occur; such
patients may progress to chronic renal insufficiency or renal failure
o Muscle and brain cells contain large amounts of CK, and damage to these cells causes enzyme to leak
into blood; presence of 5% or more of CK in blood as muscle isoform indicative of heart attack
Muscle fuel use at rest dependent on serum levels of glucose, amino acids, and fatty acids
o If blood glucose and amino acids elevated, glucose will be converted to glycogen, and branched-chain
amino acid metabolism will be high; fatty acids will be used for acetyl-CoA production and will satisfy
energy needs of muscle
o Balance between glucose oxidation and fatty acid oxidation, regulated by citrate
 When muscle cell has adequate energy, citrate leaves mitochondria and activates ACC-2, which
produces malonyl-CoA, which inhibits carnitine palmitoyl transferase-1, thereby reducing fatty
acid oxidation by muscle
 Malonyl-CoA decarboxylase inactive because AMP-PK not active in fed state
o Muscle regulates oxidation of glucose and fatty acids in part through monitoring of cytoplasmic citrate
levels
As blood glucose levels drop (as in starvation), insulin levels drop, reducing levels of GLUT4 transporters in
muscle membrane, and glucose use by muscle drops significantly; conserves glucose for use by nervous system
and RBCs
o In cardiac muscle, PFK-2 phosphorylated and activated by insulin; lack of insulin results in reduced use of
glucose by cells
o Pyruvate dehydrogenase inhibited by high levels of acetyl-CoA and NADH being produced by fatty acid
oxidation
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Fatty acids become muscle’s preferred fuel under starvation conditions
AMP-PK active because of lower than normal ATP levels, ACC-2 inhibited, and malonyl-CoA
decarboxylase activated, thereby retaining full activity of CPTI
o Lack of glucose reduces glycolytic rate, and glycogen synthesis doesn’t occur because of inactivation of
glycogen synthase by epinephrine-stimulated phosphorylation
o In prolonged starvation, muscle proteolysis induced (in part by cortisol release) for gluconeogenesis by
liver; doesn’t alter use of fatty acids by muscle for its own energy needs under these conditions
Rate of ATP use in skeletal muscle during exercise can be 100x greater than resting skeletal muscles; pathways
of fuel oxidation must be rapidly activated during exercise to respond to much greater demand for ATP
o ATP and creatine phosphate would be rapidly used up if they were not continuously regenerated
o Synthesis of ATP occurs from glycolysis and oxidative phosphorylation
o Anaerobic glycolysis especially important as source of ATP
 During initial period of exercise, before exercise-stimulated increase in blood flow and substrate
and oxygen delivery begin, allowing aerobic processes to occur
 During exercise by muscle containing predominately fast-twitch glycolytic muscle fibers because
these fibers have low oxidative capacity and generate most of their ATP through glycolysis
 When ATP demand exceeds oxidative capacity of tissue, and increased ATP demand met by
anaerobic glycolysis
o During rest, most of ATP required in all types of muscle fibers obtained from aerobic metabolism; as
soon as exercise begins, demand for ATP increases
 Amount of ATP present in skeletal muscle could sustain exercise for only 1.2 seconds if not
regenerated, and amount of phosphocreatine could sustain exercise for only 9 seconds if it were
not regenerated
 Takes longer than 1 minutes for blood supply to exercising muscle to increase significantly as
result of vasodilation and, therefore, oxidative metabolism of blood-borne glucose and fatty
acids can’t increase rapidly at onset of exercise
 First few minutes of exercise, conversion of glycogen to lactate provides considerable portion of
ATP requirement
o In fast-twitch fiber muscles, glycolytic capacity is high because enzymes of glycolysis present in large
amounts (thus overall Vmax is large)
 Levels of hexokinase are low, so very little circulating glucose used; low levels of hexokinase
prevent muscle from drawing on blood glucose to meet this high demand for ATP, thus avoiding
hypoglycemia
 Glucose-6-phosphate, formed from glycogenolysis, further inhibits hexokinase
 Tissues rely on endogenous fuel stores (glycogens and creatine phosphate) to generate ATP,
following pathway of glycogen breakdown to glucose-1-phosphate, conversion of glucose-1phosphate to glucose-6-phosphate, and metabolism of glucose-6-phosphate to lactate
 Thus, anaerobic glycolysis is main source of ATP during exercise of these muscle fibers
Anaerobic glycolysis from glycogen – glycogenolysis and glycolysis during exercise activated together because
both PFK-1 (rate-limiting enzyme of glycolysis) and glycogen phosphorylase b (inhibited form of glycogen
phosphorylase) allosterically activated by AMP
o AMP is ideal activator because its concentration normally kept low by adenylate kinase (myokinase in
muscle) equilibrium (2 ADP  AMP + ATP); thus whenever ATP levels decrease slightly, AMP
concentration increases many-fold
o Starting from molecule of glucose-1-phosphate derived from glycogenolysis, 3 ATP molecules produced
in anaerobic glycolysis, as compared with 31-33 molecules of ATP in aerobic glycolysis
o To compensate for low ATP yield of anaerobic glycolysis, fast-twitch glycolytic fibers have much higher
content of glycolytic enzymes, and rate of glucose-6-phosphate use more than 12x as fast as in slowtwitch fibers
o Muscle fatigue generally results from lowering of pH of tissue to 6.4; both aerobic and anaerobic
metabolism lowers pH
 Both lowering pH and lactate production can cause pain
o
Metabolic fatigue can occur once muscle glycogen depleted; muscle glycogen stores used up in <2
minutes of anaerobic exercise
 It is next to impossible to do pushups for more than 2 minutes because that is fast-twitch
glycolytic fibers
o Glycogen degradation in muscle not sensitive to glucagon (muscles lack glucagon receptors) so there is
little change in muscle glycogen stores during overnight fasting or long-term fasting if individual remains
at rest
 Glycogen synthase inhibited during exercise, but can be activated in resting muscle by release of
insulin after high-carb meal
 Unlike liver form of glycogen phosphorylase, muscle isozyme contains allosteric site for AMP
binding; when AMP binds to muscle glycogen phosphorylase b, enzyme activated even though
it’s not phosphorylated
 Thus, as muscle begins to work and myosin-ATPase hydrolyzes existing ATP stores to ADP, AMP
begins to accumulate (because of adenylate kinase reaction), and glycogen degradation
enhanced
 Activation of muscle glycogen phosphorylase b further enhanced by release of Ca2+ from SR,
which occurs when muscles stimulated to contract; increase in sarcoplasmic Ca2+ also leads to
allosteric activation of glycogen phosphorylase kinase (through binding to calmodulin subunit of
enzyme), which phosphorylates muscle glycogen phosphorylase b, fully activating it
 During intense exercise, epinephrine release stimulates activation of adenylate cyclase in muscle
cells, thereby activating cAMP-dependent protein kinase
 PKA phosphorylates and fully activates glycogen phosphorylase kinase so that continued
activation of muscle glycogen phosphorylase can occur; hormonal signal slower than initial
activation events triggered by AMP and calcium
o Once exercise begins, electron-transport chain, TCA cycle, and fatty acid oxidation activated by increase
of ADP and decrease of ATP
 Pyruvate dehydrogenase remains in active, nonphosphorylated state as long as NADH can be
reoxidized in electron-transport chain and acetyl-CoA can enter TCA cycle
 Even though mitochondrial metabolism working at max capacity, sometimes ATP not sufficient
enough to meet needs, and AMP begins to accumulate
 Increased AMP levels activate PFK-1 and glycogenolysis, thereby providing additional ATP from
anaerobic glycolysis (additional pyruvate produced doesn’t enter mitochondria but is converted
to lactate so that glycolysis can continue)
 Most of pyruvate formed by glycolysis enters TCA cycle, whereas remainder reduced to lactate
to regenerate NAD+ for continued use in glycolysis
o Lactate that is released from skeletal muscles during exercise can be used by resting skeletal muscles or
by heart (muscle with large amount of mitochondria and very high oxidative capacity)
 NADH/NAD+ ratio lower than in exercising skeletal muscle, and lactate dehydrogenase reaction
proceeds in direction of pyruvate formation
 Pyruvate generated converted to acetyl-CoA and oxidized in TCA cycle, producing energy by
oxidative phosphorylation
o Potential fate of lactate is that it will return to liver through Cori cycle, where it is converted to glucose
Mild and Moderate Intensity Long-Term Exercise
 Mild-to-moderate intensity exercise can be performed for longer periods than can high-intensity exercise
because of aerobic oxidation of glucose and fatty acids; release of lactate diminishes as aerobic metabolism of
glucose and fatty acids becomes predominant
 At any given time during fasting, blood contains enough to support a person running at a moderate pace for a
few minutes; therefore, blood glucose supply must be constantly replenished
o Liver produces glucose by breaking down its own glycogen stores and by gluconeogenesis
o Major source of carbon for gluconeogenesis during exercise is lactate, produced by exercising muscle,
but amino acids and glycerol also used
o Epinephrine released during exercise stimulates liver glycogenolysis and gluconeogenesis by causing
cAMP levels to increase
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During long periods of exercise, blood glucose levels maintained by liver through hepatic glycogenolysis and
gluconeogenesis; amount of glucose that liver must export is greatest at higher workloads, in which case muscle
using greater proportion of glucose for anaerobic metabolism
With increasing duration of exercise, increasing proportion of blood glucose supplied by gluconeogenesis
o For up to 40 minutes of mild exercise, glycogenolysis mainly responsible for glucose output of liver
o After 40-240 minutes exercise, total glucose output of liver decreases because of increased use of fatty
acids, which are being released from adipose tissue triacylglycerols (stimulated by epinephrine release)
o Glucose uptake by muscle stimulated by increase in AMP levels and activation of AMP-activated protein
kinase, which stimulates translocation of GLUT4 transporters to muscle membrane
Hormonal changes that direct increased hepatic glycogenolysis, hepatic gluconeogenesis, and adipose tissue
lipolysis include decrease in insulin and increase in glucagon, epinephrine, and norepinephrine
o Plasma levels of GH, cortisol, and TSH increase and may contribute to fuel mobilization
o Activation of hepatic glycogenolysis occurs through glucagon and epinephrine release
o Hepatic gluconeogenesis activated by increased supply of precursors (lactate, glycerol, amino acids, and
pyruvate), induction of gluconeogenic enzymes by glucagon and cortisol (occurs only during prolonged
exercise), and increase supply of fatty acids to provide ATP and NADH needed for gluconeogenesis and
regulation of gluconeogenic enzymes
The longer the duration of exercise, the greater the relianceof muscle on free fatty acids for generation of ATP
o Because ATP generation from free fatty acids depends on mitochondria and oxidative phosphorylation,
long-distance running uses muscles that are principally slow-twitch oxidative fibers, such as
gastrocnemius
o Resting skeletal muscle uses free fatty acids as principal fuel
o Almost anytime except postprandial state (right after eating), free fatty acids preferred fuel for skeletal
muscle; preferential use of fatty acids over glucose as fuel for skeletal muscle depends on
 Availability of free fatty acids in blood, which depends on their release from adipose tissue
triacylglycerols by hormone-sensitive lipase; during prolonged exercise, small decrease of insulin
and increases of glucagon, epinephrine, norepinephrine, cortisol, and possibly GH all activate
adipocyte tissue lipolysis
 Inhibition of glycolysis by products of fatty acid oxidation; pyruvate dehydrogenase activity
inhibited by acetyl-CoA, NADH, and ATP, all of which are elevated as fatty acid oxidation
proceeds; as AMP levels drop and ATP levels rise, PFK-1 activity decreased
 Glucose transport may be reduced during long-term exercise; glucose transport into skeletal
muscles via GLUT4 transporter greatly activated by either insulin or exercise; during long-term
exercise, effect of falling insulin levels or increased fatty acid levels may counteract stimulation
of glucose transport by exercise itself
 Oxidation of ketone bodies increases during exercise; use of ketone bodies as fuel dependent on
their rate of production by liver; ketone bodies never major fuel for skeletal muscles (muscles
prefer free fatty acids)
 Acetyl-CoA carboxylase (isozyme ACC-2) must be inactivated for muscle to use fatty acids;
occurs as AMP-PK activated and phosphorylates ACC-2, rendering it inactive, and activates
malonyl-CoA decarboxylase, to reduce malonyl-CoA levels and allow full activity of CPTI
Branched-chain amino acid oxidation estimated to supply max of 20% of ATP supply of resting muscle
o Oxidation used to generate ATP and synthesize glutamine, which effluxes from muscle
o Highest rates of branched-chain amino acid oxidation occur under conditions of acidosis, in which there
is higher demand for glutamine to transfer ammonia to kidney and to buffer urine as ammonium ion
during proton excretion
o Glutamine synthesis occurs from carbon skeletons of BCAA oxidation (valine and isoleucine) after initial
five steps of oxidative pathway
Exercise increases activity of purine nucleotide cycle, which converts aspartate to fumarate plus ammonia
o Ammonia used to buffer proton production and lactate production from glycolysis
o Fumarate recycled and can form glutamine
Acetate – excellent fuel for skeletal muscle; treated by muscle as very short-chain fatty acid
o
Activated to acetyl-CoA in cytosol and transferred into mitochondria via acetylcarnitine transferase
(isozyme of carnitine palmitoyl transferase)
o Sources of acetate include diet (vinegar) and acetate produced in liver from alcohol metabolism
o Certain power bars for athletes contain acetate
Metabolic Effects of Training on Muscle Metabolism
 Effect of training depends, to some extent, on type of training
 In general, training increases muscle glycogen stores and increases number and size of mitochondria
o Fibers increase capacity for generation of ATP from oxidative metabolism and ability to use fatty acids as
fuel
o Winners in marathon races use muscle glycogen more efficiently than others
 Training to improve strength, power, and endurance of muscle performance – resistance training
o Goal is to increase size of muscle fibers (hypertrophy)
o Hypertrophy occurs by increased protein synthesis in muscle and reduction in existing protein turnover
Biochemical Comments – the SERCA Pump
 SERCA pump – transmembrane protein present in several different isoforms throughout body
 Encoded by 3 genes (SERCA1, SERCA2, and SERCA3)
o SERCA1 – produces 2 alternatively spliced transcripts
 SERCA 1b is expressed in fetal and neonatal fast-twitch skeletal muscles and is replaced by
SERCA1a in adult fast-twitch muscles
o SERCA2 – undergoes alternative splicing, producing SERCA2b (expressed in all cell types and associated
with IP3-regulated calcium stores) and SERCA2a (primary isoform expressed in cardiac tissue)
o SERCA3 – produces at least 5 different alternatively spliced isoforms, which are specifically expressed in
different tissues
 SERCA2a plays important role in cardiac contraction and relaxation
o Contraction initiated by release of Ca2+ from intracellular stores, whereas relaxation occurs as Ca2+ resequestered in SR, in part mediated by SERCA2a protein
o SERCA2a pump regulated in part by its association with protein PLN
o PLN associates with SERCA2a in SR and reduces its pumping activity
o Because new contractions can’t occur until cytosolic Ca2+ has been re-sequestered into SR, reduction in
SERCA2a activity increases relaxation time
o When called on, heart can increase rate of contractions by inhibiting activity of PLN (phospholamban)
through phosphorylation of PLN by PKA
o Epinephrine release stimulates heart to beat faster through epinephrine binding to its receptor,
activating a G protein, which leads to adenylate cyclase activation, elevation of cAMP levels, and
activation of PKA
o PKA phosphorylates PLN, thereby reducing its association with SERCA2a and relieving inhibition of
pumping activity, resulting in reduced relaxation times and more frequent contractions
 Mutations in PLN lead to cardiomyopathies, primarily an autosomal dominant form of dilated cardiomyopathy
o Mutant PLN forms inactive complex with PKA and blocks PKA phosphorylation of PLN
o Patients develop cardiomyopathy in their teens
o Cardiac muscle doesn’t pump well because of constant inhibition of SERCA2a and becomes enlarged
(dilated); because of poor pumping action of heart, fluid can build up in lungs
o Pulmonary congestion results in sense of breathlessness (left heart failure)
o Eventually, progressive left heart failure leads to fluid accumulation in other tissues and organs of body,
such as legs and ankles (right heart failure)