BS3050 Physiology of Sport and Exercise
Muscle Metabolism
Aims: to explain how ATP is generated for muscular contraction and the factors
which limit and regulate the availability of ATP in the muscle cell
Learning Outcomes:
An understanding of the role of ATP in muscle contraction
Knowledge of the sources and use of ATP in muscle contraction: Alactic and lactic
anaerobic sources and aerobic sources.
An understanding of the roles of glycolysis, citric acid cycle, oxidative
phosphorylation and -oxidation in the provision of energy
Molecular Mechanism of Skeletal Muscle Contraction
The major proteins involved in muscle contraction are actin and myosin which are
assembled into filaments that undergo transient interactions and slide past each other
to bring about the contraction. This process requires ATP, which is consumed in the
process with the concomitant formation of ADP and inorganic phosphate (Pi). I will
not go into the detailed mechanism but just explain how ATP is consumed during the
contractile process and what effect this has on the metabolism within the muscle.
Some Basic facts about muscle contraction:
 The signal from the nerve triggers an action potential in the muscle cell plasma
membrane.
 The signal is relayed to the sarcoplasmic reticulum (sr), a sheath of anastomosing
vesicles forming a network which surrounds each myofibril
 Muscle contraction is initiated by a sudden but transient (less than 30 millisec)
rise in cytosolic Ca2+ which is released from the sr
 Ca2+ changes are detected by a protein called troponin C which interacts with the
actin filaments and initiates the contraction
 In the resting state the interaction between actin and myosin is inhibited but when
cytosolic Ca2+ increases then ATP can bind to the myosin which has ATPase
activity (ATP  ADP + Pi)
 The ATP binding causes a change in conformation of the myosin head causing it
to move along the actin filament but the hydrolysis of ATP causes the myosin to
regain its original conformation generating the power stroke.
 Thus a molecule of ATP is consumed for every binding event and conformational
change at multiple points of contact between myosin and actin moves the
filaments with respect to one another and therefore the muscle contracts.
 Each cycle the consumption of 1 molecule of ATP generates about 3 – 4
pNewtons (1 Newton = Kg.m.s-2 ) of force and moves the filaments about 5 – 10
nm relative to one another.
Phosphoryl Transfer Potential of ATP
The standard free energy of hydrolysis of ATP and other metabolites, which is a
convenient method of measuring the ‘energy’ associated with different metabolites
(see Table 14.1), reveals that ATP is not the intermediate with the highest phosphoryl
transfer potential but its properties allow it to function efficiently as a carrier capable
of transferring energy from one molecule to another. ATP is therefore an immediate
donor of energy which is very rapidly turned over. The total ATP in the body at any
one time is only about 100g yet a resting individual consumes about 280 g ATP per
minute rising to about 500 g per minute on strenuous effort. In a marathon 60 kg of
ATP may be consumed!
Muscle energy ( i.e. ATP) is derived from 3 main sources:
Alactic Energy Source
(it is called alactic because lactic acid does not accumulate in the muscle)
Anaerobic source (for up to about 30 sec depending on the intensity of effort)
This source is mainly used for explosive sports such as sprinting, javelin, discus,
weightlifting, golf swing, tennis serve, kicking a football, diving etc. The capacity is
about 23 - 36 kJ with maximum power output of 4 - 12 kW for about 8 sec.
The ATP source for this phase is via the cytoplasmic ATP present in the muscle
cytoplasm and that generated from creatine phosphate in an anaerobic step catalysed
by creatine kinase:
Creatine Phosphate + ADP  Creatine + ATP G0 = -8kJ/mol
i.e. the equilibrium lies well to the right and this maintains the muscle adenylate
(ATP, ADP and AMP) pool in the ATP form. In the resting muscle the relative
concentrations are: ATP (4mM), ADP (0.13mM), Creatine phosphate (25mM) and
creatine (13mM) and When explosive muscle contraction occurs it is initially the ATP
which is utilised closely followed by the creatine phosphate. In a 100 meter sprint, the
ATP in muscle is sufficient for less than 1 sec whilst the regeneration of ATP by
creatine phosphate is sufficient for about 4 sec of effort and the remainder of the race
is dependent on anaerobic glycolysis. NMR studies on contracting muscle shows that
creatine phosphate content is depleted by about 90% while the ATP content is
maintained. Because of the varied roles of ATP in cells it would not be desirable for
the ATP to become too depleted. Creatine phosphate is resynthesised by the creatine
phosphate shuttle which exchanges creatine phosphate synthesised in the
mitochondria for the creatine in the cytoplasm. A second reaction can provide ATP
catalysed by myokinase:
2ADP   ATP + AMP
This reaction is at equilibrium and is therefore driven to the right by ATP
consumption. The reaction can even be driven further to the right by the deamidation
of AMP to IMP but this depletes the adenylate pool.
After a rest of a few minutes the ATP and creatine phosphate can be restored to their
resting levels by aerobic metabolism.
Lactate-generating Anaerobic source of ATP
This source is used for short spells of strenuous effort lasting less than 3 minutes as in
gymnastics, 200 – 800 metre races in athletics, 100 – 200 metre races in swimming
events. The capacity of the muscles for such effort is about 95 – 120 kJ and the
maximum power output is approx. 3 – 4 kW but this cannot be sustained for more
than a minute or so. After this effort it can take 1 to 2 hrs to recover depending on the
fitness of the individual.
This source of energy depends on the glycogen degradation and the rate of glycolysis
in the muscle, which generates ATP from ADP, and results in the accumulation of
lactate and H+ ions which accumulate in the cytoplasm. Lactate cannot be utilised
quickly enough by the muscle mitochondria and hence it accumulates but it is the fall
in pH in the muscle cytoplasm (rather than lactate accumulation per se) which
decreases the efficiency of contraction of muscle. This process is self-limiting because
the acidosis builds up before the glycogen has been completely utilised. The
accumulation of H+ ions appears to inhibit various enzymes involved in the provision
of ATP rather than have a direct effect on the contractile mechanism although an
accumulation of Pi does have a direct effect.
H+ ions are removed via the blood stream where they are ‘mopped up’ by the
Bicarbonate/Carbonic Acid buffering system. The lactate can be converted back into
glucose via a process known as gluconeogenesis but this can only occur in the liver
and hence lactate accumulates in the blood circulation after exercise. It should be
emphasised that lactate itself is not toxic it is a by-product of anaerobic glycolysis,
which is rich in energy and indeed is a vital intermediate which can be used by many
tissues but not used very efficiently by skeletal muscle in the short term. The lactate
concentration in the blood is sometimes used as a marker to measure muscle function
but it is a very indirect and inaccurate way of measuring muscle acidosis. There is a
concept of an ‘anaerobic threshold’ of 4mM lactate where the muscle has to switch to
aerobic metabolism to supply ATP but in reality this has little or no validity.
There is a limited store of glycogen in muscle –it makes up about 1.5% of the wet
weight of the muscle in a rested individual i.e. about 420g in 28 Kg of muscle found
in a standard 70 Kg man. An additional glycogen store of about 500 g is found in the
liver: this is used to maintain blood glucose in the short term. Glycogen is
metabolised by the enzyme phosphorylase
Glycogen(n) + Pi  Glycogen(n-1) + Glucose-1-phosphate.
Glucose-1-phosphate can be readily converted to Glucose-6-phosphate, which can be
readily converted to lactate by anaerobic glycolysis. An alternative source of Glucose6-phosphate is the uptake of glucose from the blood via a transporter (Glut4 – insulindependent) in the muscle plasma membrane and its phosphorylation by hexokinase.
This is a relatively slow process and requires the expenditure of ATP.
Phosphorylase is present in the cytoplasm but anchored to the sarcoplasmic reticulum
and becomes activated very rapidly in response to the increase in cytoplasmic Ca2+
which is the signal for muscle contraction. Hence muscle contraction is very closely
coupled to the supply of glycolytic intermediates which can be used immediately to
generate ATP.
McArdles disease, an inherited deficiency of muscle phosphorylase, results in
inability to perform strenuous efforts results in painful muscular cramps. No
accumulation in H+ or lactate but NMR studies indicate that there is an increase in
ADP on exercise which correlates with the onset of cramps.
Anaerobic Glycolysis
Conversion of glycogen or glucose to pyruvate and lactate (Fig 16.3)
Occurs in 3 stages :
(a) Conversion of Glucose or glycogen to fructose 1,6-bisphosphate. This requires an
input of energy in the form of ATP (either 2 ATP in the case of glucose or 1ATP
for glycogen)
(b) Cleavage of the 6-carbon sugar to give two molecules of the high energy
intermediate 1,3 bisphosphoglycerate
(c) The generation of ATP by phosphoglycerate kinase and puruvate kinase
Overall 2 molecules of ATP are consumed and 4 molecules of ATP produced ( i.e.
net 2 mol ATP) during anaerobic glycolysis of glucose whilst glycolysis from stored
glycogen yields 3 mol of ATP. Therefore in the short term, glycogen produces more
energy than glucose.
Why does lactate accumulate?
Lactate accumulates in the anaerobic muscle because of the reductant, NADH, which
is produced at an earlier step in glycolysis, reacts with pyruvate to form lactate which
accumulates at high concentrations until it can be removed. This reaction is catalysed
by lactate dehydrogenase:
Pyruvate + NADH   Lactate + NAD+
Lactate can be removed by conversion to pyruvate and the metabolism of the latter by
the Citric acid cycle by muscle mitochondria but before this can happen the
accumulated NADH must also be removed by the mitochondria. A second mechanism
for the removal of lactate (which does not depend on the removal of muscle NADH)
involves the Cori Cycle in which lactate is transported to the liver where it can be
reutilized to make glucose by the process of gluconeogenesis.
Aerobic Mitochondrial Generation of ATP
For longer periods of exercise lasting more than 3 minutes: middle and long distance
running, football and hockey matches etc the main source of energy is from aerobic
sources with perhaps bursts from anaerobic sources. The capacity of the muscles for
such effort is almost unlimited a but the maximal power is only of the order of 1 - 2
kW, and rather limited over the longer time period. The recovery time after such
exercise may be 24 - 48 hr.
Aerobic power depends on the ability of an individual to (a), absorb, (b), transport and
(c), utilize oxygen. In turn (a) and (b) are a function of the efficiency of the lungs and
cardiovascular system whilst (c) is dependent on the number and volume of the
muscle mitochondria. Aerobic endurance ultimately depends on the ability of the
mitochondria to utilize oxygen in the oxidation of cellular substrates to CO2 and H2O
The carbohydrates represent 50 – 60% of the aerobic substrates mainly in the form of
glucose (4 –5 mM, fasting level) circulating in the blood and glycogen, the polymeric
form of glucose which is stored in an inert form in the muscle cytoplasm (1.5 - 2% of
total weight in the resting muscle). The total energy available in the circulating
glucose is 170 – 250 kJ while the muscle glycogen stores represent about 2500 - 5000
kJ. Most other carbohydrates in the diet need to be transformed into glucose, and then
to glycogen, before they can be used by muscle
The lipids represent about 25 – 30 % of the anaerobic energy consumption. Storage
fat is in the form of triacylglycerol which is an ester made of glycerol (a glycolytic
intermediate) and fatty acids. These fatty acids may be absorbed in food or
synthesised in the liver or adipose tissue and stored as triacylglycerol. This reserve is
large (420,000kJ in adipose tissue) in most people although it clearly varies from
person to person – even the supremely fit have 5 - 20 % of body weight. In order to be
utilised these fatty acids have to be mobilised and used by mitochondria by a process
of -oxidation to generate ATP. This oxidation requires more oxygen than the
metabolism of carbohydrate but generates much more ATP (see later) and thus more
power.
The link between glycolysis and the citric acid cycle is irreversible
The citric acid cycle is the final common pathway for the aerobic oxidation of fuel
molecules. Entry of substrates into the cycle is via Acetyl CoA which is formed from
pyruvate in the mitochondria by an enzyme complex known as pyruvate
dehydrogenase:
Pyruvate + Coenzyme A + NAD+  AcetylCoA + CO2 + NADH
This is an irreversible reaction in humans (indeed in all animals); once acetyl CoA is
formed it can only be used for two main purposes: generation of energy via the citric
acid cycle or conversion to fat which can be laid down in adipose tissue until required.
The Citric Acid Cycle and Oxidative Phosphorylation
For the complete oxidation of the glycolytic product, pyruvate to CO2 and H2O
requires the function of mitochondrial metabolic cycle - the citric acid cycle (Fig
17.15). The fuel substrate is acetyl CoA which is converted to CO2 . The citric acid
cycle requires a supply of the intermediate oxaloacetate to combine with Acetyl CoA
to give citrate, in a series of oxidation reactions which yield GTP, NADH and
FADH2. The latter two are also energy-rich molecules because they contain a pair of
electrons having a high transfer potential (i.e. they are strong reductants). These can
be used to generate ATP by the process of oxidative phosphorylation as the result of
the transfer of these electrons to O2 via a series of electron carriers. This generates a
gradient of H+ across the inner mitochondrial membrane which is used to drive ATP
synthesis from ADP and Pi. The rate of oxidative phosphorylation is determined by
the need for ATP as indicated by the accumulation of ADP and the availability of
oxygen to the mitochondria.
Table 18.4 shows the ATP yield from the complete oxidation of glucose.
For every molecule of glucose converted to CO2 :
2 mols of ATP are generated by glycolysis, 2 mol of ATP by the operation of the
citric acid cycle and the remaining 26 mol ATP by oxidative phosphorylation.
Generation of energy from fat
As the immediate sources of energy ATP, carnitine phosphate and glycogen become
depleted the muscle turns to another source of energy triacylglycerol, which becomes
very important in endurance events. Blood glucose remains available but this is
necessary to maintain the function of all the other tissues in the body e.g. the brain,
and so can only be used sparingly in muscles. Endurance training increases the
individual’s capacity to mobilise, deliver and oxidise fatty acid derived from
triacylglycerol stored in the adipose tissue.
Mobilization of triacylglycerol involves hydrolysis with the release of fatty acids
(and glycerol). Fatty acids are long chain hydrocarbon acids which are transported in
the blood stream as a complex with albumin to the sites where they can be
metabolised, including muscle, by a process of -oxidation which yields Acetyl CoA,
which can enter the citric acid cycle and produce energy as described. The utilization
of Acetyl-CoA derived from fat does require some metabolism of carbohydrate as
well to replenish the pool of oxaloacetate which is essential for the operation of the
citric acid cycle. In addition -oxidation also yields NADH and FADH2 which can
also be harnessed to make ATP via oxidative phosphorylation. The complete
oxidation of a single molecule of palmitic acid yields 106 molecules of ATP (c.f. 30
molecules for glucose) and hence fat is a much more efficient storage form of energy
although it is not immediately accessible for muscular work.
The percentage of energy supplied by fatty acids varies from about 30 to 80 %
according to the nutritional state, the intensity of training and the intensity of physical
training and becomes the primary source in endurance events. Furthermore exposure
to low carbohydrate diets accentuates the dependence on fatty acids because the
muscle adapts to using this source to generate ATP.
-oxidation of fatty acids by the liver can also generate ketone bodies (e.g.
acetoacetate) which can also be used by skeletal muscle to generate Acetyl CoA and
therefore ATP. Cardiac muscle, in particular, is dependent on a continuous supply of
ketone bodies as a fuel source, which clearly needs a reliable and constant source of
energy!
Generation of energy from proteins
Proteins also play a role as energy yielding substrates during endurance training and
heavy physical work. Proteins, mainly in muscle and liver can be mobilized in the
form of aminoacids, which then undergo deamination to convert them into products
which can be metabolised via the glycolysis and citric acid cycle. Some amino acids
are converted to pyruvate, others to acetyl CoA whilst others enter the citric acid
cycle directly.
Skeletal Muscle Fibre Types
Voluntary skeletal muscle is under conscious control. Each fibre is an enormous,
multi-nucleate cell, formed by fusing hundreds of myoblasts end-to-end. They show a
striated pattern, reflecting the regular arrangement of sarcomeres within each cell.
Type I fibres : depend on oxidative metabolism, slow twitch, relativly low ATPase.
The contraction cycle procedes at a relatively slow pace. The fibres have high aerobic
capacity but low anaerobic capacity. Used in endurance exercise and maintaining
posture – resistant to fatigue. Dark red in colour because of the presence of
myoglobin, and the highly vascularized tissue, with large mitochondria.
Type II fibres: glycolytic, fast twitch, high anaerobic capacity, recruited for higher
intensity exercise in addition to type I
 Type IIa fast twitch, react more quickly than Type I, ATP hydrolysed more
quickly by ATPase in myosin. They have both aerobic and anaerobic metabolisms
well developed and are moderately fatigue-resistant. Their level of stored
glycogen is high, hence capable of anaerobic glycolysis. The fibres are active in
walking and sprinting.
 Type IIb very fast twitch, hydrolyse ATP very rapidly, almost devoid of
mitochondria, blood vessels and myoglobin (hence white). High glycogen content
- The fibres have a high anaerobic capacity, recruited for very intense efforts
(weight lifting, throwing etc.) and fibres fatigue very quickly. Training can
increase the volume of these fibres via the synthesis of new muscle proteins.
Relative proportion of different types of fibre is genetically determined and helps to
account for difference between individuals athletic performances but characteristics of
fibres can be changed to some extent by training.
Chickens use their legs (red meat) for walking and standing for long periods of time, whilst their wings
(white meat) are used for brief bursts of activity during flying. This perfectly illustrates the differences
between fast and slow-twitch fibres. In mammals the different types of fibre coexist in each muscle.
References:
Exercise Physiology 5th ed. (2001) McArdle, Katch and Katch Chapters 5, 6 and & 7
612.044 MAC ( Bedford Library Quarto Holdings)
Physiology of sport and exercise (1999) Wilmore, Jack H. 612.044 WIL( Bedford
Library Quarto Holdings)
Biochemistry 5th Ed (2002) Berg, Tymockzo and Stryer Chapters 14, 16, 18 and 22.
(any basic Biochemistry textbook published in the last 10 years will suffice)
British Medical Bulletin Vol 48 (3) Sports Medicine p 477 – 95, 569-91
Basic and Applied Sciences for Sports Medicine ( Bedford Library Journal Section)
Human Anatomy and Physiology (2003) Marieb
PowerPoint slides on muscle contraction
http://www.aw-bc.com/ppt/marieb_hap/chap09c.ppt