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Introduction: These lectures focus on three aspects of muscle biochemistry:
Most students have covered some aspects of muscle contraction in their school biology course, but to varying extents. We will briefly recapitulate the main points below. If this material is completely unfamiliar then you must study the muscle chapters in a basic biochemistry or physiology textbook, to ensure that you are up to speed with the other members of the class.
Voluntary, skeletal muscles show a repeating, striated pattern under the light microscope and the principal features were named for their optical properties: the "I" bands (for isotropic) have almost the same refractive index in all directions, but "A" bands (for anisotropic) have different refractive indices along and across the fibres. The repeating unit is called a "sarcomere". In relaxed muscles the sarcomeres are about 2 microns long, but some of the bands move closer together as the muscle shortens.
The "A" bands maintain a constant length, but the "I" bands vary in size as the muscle changes length.
The "A" bands contains thick filaments composed mainly of the protein myosin, while the "I" band contains thin filaments that are rich in the common cytoskeletal protein actin. The two sets of filaments slide relative to each other when the muscle contracts. Sarcomeres are symmetrical structures, and many thousands are aligned end to end along the length of the muscle. Note the Z-line, which holds all the thin filaments together at the ends of the sarcomeres, and the M-line, which holds all the thick filaments together in the middle of each sarcomere.
Individual myosin molecules resemble two-headed tadpoles: two catalytically active head groups are attached to a long, largely helical tail. Each thick filament contains about 250 myosin molecules, with the tails wrapped together along the shaft of the thick filament. The head groups are exposed on the surface, where they can interact with actin in the thin filaments in the presence of calcium ions released from the sarcoplasmic reticulum.
The energy for muscle contraction comes from the hydrolysis of ATP. Myosin head groups attach temporarily to the actin, after which a conformational change in the myosin drags the filaments in opposite directions. Binding a fresh molecule of ATP releases the myosin from the actin, so that the cycle can be repeated many times during a single muscle twitch. Click here to see an animated video of the process.
Here is an alternative website that makes many of these points. Click the cartoons and animated diagrams for more information. You might prefer another set of lecture notes on the same topics.
All the muscles in the human body show biochemical specialisation which allows them to perform their particular physiological functions. The eyeballs are steered by extra-ocular muscles when reading: they must contract quickly and precisely, but the muscles in your back and buttocks evolved for continuous heavy lifting where fuel economy is important. The hollow viscera often require a slow steady squeeze to function properly. We normally recognise three basic types of vertebrate muscle:
1) 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.
2) Cardiac muscle is similar to skeletal muscle, but is not under conscious control. These mono-nucleate cells are much smaller, but still show a striated pattern.
3) Smooth muscle is closer to non-muscle cells. No regular striations are visible and the contractions are much slower. Smooth muscle is found in the blood vessels, gut, skin, eye pupils, urinary and reproductive tracts.Back to the table of contents
Muscles use a wide variety of fuels, although most muscles have preferred sources of energy. There are considerable species and anatomical differences, and variations between adjacent cells. Insect flight muscles, for example, are among the most metabolically active tissues known. They differ substantially in subcellular structure from vertebrate muscles, they have a different system for oxygen and substrate delivery and a different energy-yielding metabolism. Even among mammals and birds we find very considerable variation. We return to this topic below.
Muscle metabolism accelerates by several orders of magnitude when switching from the resting to the active state. This is associated with very considerable increases in blood flow and oxygen demand. These mechanisms are essential for survival: if they were not present then large amounts of food energy would be wasted, animals would over-heat, and the heart could not pump sufficient blood to fully perfuse every muscle capillary bed at maximal rates. The system only works because of highly selective delivery of resources exactly where they are needed.
High concentrations of oxygen are toxic to most cells. They damage subcellular constituents, leading to premature ageing and cell death. Vertebrate blood flow is regulated by oxygen demand to supply just enough oxygen to meet each cell's needs, with hardly any left over to damage the fabric of the muscle. This restriction may limit the availability of substrates other than oxygen (for example, glucose and free fatty acids) to the muscle tissue. Insects also severely restrict oxygen delivery, using muscular sphincters at the openings of their respiratory trachea.
Oxygen uptake is governed by ATP utilisation. In resting muscle, where ATP turnover is very slow, the mitochondria do not use very much oxygen. The pre-capillary sphincters contract, and blood flow shuts down to a basal level that supplies just sufficient oxygen for cellular needs. Muscle blood flow is indirectly controlled by energy ultilisation and ATP demand. We will examine some of the control mechanisms below.
Most ATP is ultimately generated by mitochondrial respiration. (There are exceptions which are dealt with below.) The ATP is actively pumped out of the mitochondria, against a concentration gradient, using the electrical potential across the inner mitochondrial membrane as the driving force. At the same time, ADP is actively taken up by the mitochondria, keeping the cytosolic [ADP] very low. The cytosolic ATP:ADP is at least 200:1.
This means that the important ATP/ADP couple is displaced further from equilibrium in the cytosol than it is in the mitochondria, which has three important consequences for muscle metabolism:
"Supercharged" ATP gives a competitive edge to muscle metabolism, and elaborate mechanisms have evolved to protect and enhance this advantage. Diffusion rates within cells very directly with metabolite concentrations. ATP is normally present in large amounts, and subcellular diffusion of ATP is not an issue, but there is a serious problem "recycling the empties" quickly enough because the intracellular concentration of ADP is (and must be) very low.
Creatine, creatine phosphate and creatine kinase are used to overcome this problem. Creatine phosphate is a better phosphoryl donor than ATP. This means that (at normal cellular energy levels) the ratio between creatine and creatine phosphate is nearly 1:1 so that there are plenty of empty bottles (creatine) to bring the "spent" ATP back from the myofibrils, without needing to transport any ADP.
Creatine is a normal constituent of meat, because domestic animals face exactly the same metabolic challenges that we do. Many athletes consume additional creatine as a legal dietary supplement, hoping to enhance their muscle performance. However, there is normally plenty of creatine around anyway, and it is far from clear that this supplementation does any good.
Adenine nucleotide (AMP, ADP & ATP) concentrations are related by the enzyme myokinase, which catalyses the freely reversible reaction:
The myokinase equilibrium constant is close to 1 under physiological conditions. This implies that:
The free cytosolic ADP concentration is normally very low in resting muscle, because ADP is actively taken up by mitochondria in exchange for ATP. The corresponding AMP concentration is vanishingly small, but it rises very rapidly on exercise, as soon as the ADP concentration starts to increase. This makes cytosolic 5' AMP an exquisitely sensitive indicator of the cellular energy supply in all types of muscle, and indeed in all other tissues as well.
Linear 5' AMP (not 3'5' cyclic AMP) is a major allosteric activator for glycogen phosphorylase and phosphofructokinase, and is also the immediate precursor for the local hormone adenosine, a powerful vasodilator which increases blood flow to rapidly metabolising tissues.
Linear 5' AMP is an activator for AMP-activated protein kinase [AMPK] which stimulates glucose uptake by skeletal muscle during exercise and under conditions of metabolic stress. (Please don't try to study the linked paper - except perhaps for the introduction - it has been included to the show the cutting edge of current research.) AMPK is itself a substrate for yet another kinase (AMP kinase kinase) and appears to play a major role in type 2 diabetes. Try not to confuse AMPK with protein kinase A (which responds to 3'5' cyclic AMP) since their functions are entirely different. AMPK protects cells from stresses causing ATP depletion by switching off ATP-consuming biosynthetic pathways, whereas PKA is part of a hormonal second messenger system, and is discussed in relation to the Cori cycle below.Back to the table of contents
The purine nucleotide cycle is an unusual feature of skeletal muscle, which serves to replenish TCA cycle and glycolytic intermediates when the energy demand is high. AMP is deaminated to yield inosine monophosphate (IMP) which is converted to adenylosuccinate and then back to AMP. The net effect is an AMP-dependent conversion of aspartate to fumarate and ammonia whenever the mechanical work load increases. The process can be used repeatedly because the aspartate pool is many times larger than the pool of TCA intermediates and is constantly replenished from the blood or the internal muscle protein stores.
There is no need to learn this pathway, which is provided to illustrate the point. You might remember that ammonia is produced by exercising muscles, and has been measured in the sweat of high-class rugby players after an important match.Back to the table of contents
The principal fuels for muscle contraction are carbohydrates and fats. Both are normally oxidised to carbon dioxide and water, although there is a small contribution from anaerobic glycolysis as described below. Fats are the most economical fuel source, but limitations on fat delivery rates means that carbohydrates must be used at higher work outputs.
Free fatty acids, when available, suppress the oxidation of carbohydrates through the following mechanisms:
Although oxidative phosphorylation in mitochondria accounts for the bulk of muscular ATP generation, some fibres can generate additional ATP from anaerobic glycolysis from glycogen into lactate. This process is very much less efficient than mitochondrial ATP synthesis, but is important for sprinters and for all competitors in "explosive" athletic events, such as jumps and shot put. Most muscles cannot process the resulting lactate, which must be returned to the liver where it is recycled into glucose. This circulation of glucose from liver to muscle with lactate moving in the reverse direction, is known as the Cori cycle after the young husband and wife team who first discovered it over eighty years ago.
The Cori cycle poses some interesting regulatory problems, because it requires glycolysis to be activated in exercising muscle, whereas the opposite process, gluconeogenesis, is activated in the liver. This is achieved by a most ingenious metabolic switch:
In resting cells these interlocking "futile" cycles continue to operate at a slow rate, "wasting" a tolerably small amount of ATP, and basically going nowhere. There is no net flux in either direction, which is exactly what the organism requires. (PEP = phosphoenolpyruvate, an intermediate towards the lower end of the glycolytic pathway.)
In all tissues, any threat to the cellular energy supply promptly raises linear 5' AMP and directly switches on glycolysis using phosphofructokinase 1 (PFK1). This eventually restores ATP production to the required level. Conversely, when [ATP] is high and there are adequate levels of TCA cycle intermediates, a rise in [citrate] switches glycolysis off again.
In liver the system is also regulated by adrenalin, which raises 3'5' cyclic AMP, thereby phosphorylating and switching the "tandem" enzyme PFK2/FBPase2 into the phosphatase mode. The reduces the concentration of fructose-2,6-bisphosphate, which change inhibits PFK1 and switches on the gluconeogenic pathway via fructose-1,6-bisphosphatase.
In muscle the 3'5' cyclic AMP effect is not present. Moreover, the activity of fructose-1,6-bisphosphatase is much lower in muscle than it is in liver, so muscle can really only do glycolysis, and its capacity for gluconeogenesis is severely limited. These adaptations allow adrenalin to drive glucose production in the liver, without compromising the ability of skeletal muscle to break down glucose during exercise.Back to the table of contents
This important mitochondrial enzyme is the final "committed" step at the end of the glycolytic pathway. Up to this point it is always possible to get back to glucose, but once through PDH there is no return. PDH is regulated by a kinase / phosphatase cycle, but being located inside the impermeable mitochondrial inner membrane, it is not accessible to 3'5' cyclic AMP.
PDH activity is inhibited by ATP, Acetyl CoA and NADH, and activated by calcium ions. This allows fatty acids (which generate ATP, Acetyl CoA and NADH) to inhibit PDH and block the oxidation of carbohydrates when adequate fat supplies are available. Nevertheless the enzyme is always available to meet a sudden increase in metabolic demand, which is often signalled by a sharp rise in the intracellular calcium concentration.
It makes very good sense for most tissues to preferentially oxidise fat. Fats are an efficient store of energy, which are much less trouble to carry around than the equivalent quantity of carbohydrate. Unfortunately fats do not easily cross the blood-brain barrier, and can only be delivered to muscle tissues at a limited rate. It is therefore necessary to maintain a residual carbohydrate supply so that the brain can continue to function, and muscles can cope with a maximal energy demand.
|property||fats and oils||carbohydrates|
|energy content (kJ/gram)||37 kJ/gram||16 kJ/gram|
|percent water in vivo||zero||about 80%|
A typical human being has energy reserves totalling about 500MJ. How much extra would we weigh if this were all stored as glycogen? Some plants store oils in their seeds or in their fruit, but store carbohydrate in their roots and tubers. Suggest some reasons why this might have evolved.Back to the table of contents
Liver glycogen provides a short-term source of carbohydrate for emergency use. It is mobilised by adrenalin and glucagon, signalling via calcium ions and 3'5' cyclic AMP, but the total reserve is only sufficient for a few hours use. Adipocytes provide the major energy store in humans, but muscle proteins are also degraded when food intake is inadequate. Most amino acids [except for leucine and lysine] are glycogenic: their carbon skeletons can be converted (at least partially) into glucose via Krebs cycle intermediates. Fatty acids cannot be converted into glucose, but triglyceride droplets contain 6% by weight glycerol, which the liver converts into sugar phosphates. The glycerol component is crucial for survival.
These figures are for a 70kg male. [MJ = MegaJoules: 1 MJ will keep a 2kW electric kettle boiling for 8.3 minutes.] Typical daily energy intakes are about 12 MJ per day for males, 9.2 MJ for females, so the total stores would last about 40 days, providing water is available and blood glucose can be maintained through gluconeogenesis. In practice food withdrawal may not be complete, and reduced physical activity lowers the fasting energy requirements. Human beings have evolved to withstand a bad winter in a primitive hunter-gatherer society.Back to the table of contents
No matter how hard we train, there are limits to the amount of muscle we can grow. Also, training (and especially running) makes people feel good, and reduces their chance of suffering a heart attack. The explanation for both effects probably involves cytokines - small protein hormones produced by most cells, including muscle, that affect other tissues in the body.
Myostatin is produced by muscle tissue and plays a major role in embryonic development. It also regulates muscle growth in adults by inhibiting the transformation of stem cells into mature muscle. Muscle myostatin gene expression is transiently reduced by resistance training, permitting an increase in muscle mass, but myostatin production subsequently recovers so there is a limit to the growth than can be achieved. Large muscles might seem attractive, but there is good evidence that the amount of muscle on a "normal" animal is almost ideal, and that increases in muscle mass lead to reductions in overall biological fitness.
Interleukin 6 (IL6) is an important regulator of the immune system. It used to be considered a "pro-inflammatory" cytokine that controlled the early "acute phase" response to infection. Nowadays it is seen to have a more subtle role, modulating the immune response, and preventing over-reaction by the immune system. Recent work has shown that skeletal muscle is a major source of IL6 and that exercise massively increases IL6 output. This may be important, because depression, type 2 diabetes and cardiovascular disease are now considered to have low-grade inflammatory components. People who take regular exercise may keep their immune systems in better balance, and thereby reduce their risk of mental illness and cardiovascular disease.Back to the table of contents
Voluntary muscles contain a variety of fibre types which are specialised for particular tasks. Most muscles contain a mixture of fibre types although one type may predominate. The pattern of gene expression within each voluntary muscle cell is governed by the firing pattern of its single motor neurone. Motor neurones branch within their target muscle and thereby control several muscle fibres, called a motor unit. The high precision eye muscles have only a few fibres in each motor unit, but the muscles in your back have thousands. All the cells in a motor unit contract in unison and they all belong to the same fibre type:
Type 1 or slow oxidative fibres have a slow contraction speed and a low myosin ATPase activity. These cells are specialised for steady, continuous activity and are highly resistant to fatigue. Their motor neurones are often active, with a low firing frequency. These cells are thin (high surface to volume ratio) with a good capillary supply for efficient gas exchange. They are rich in mitochondria and myoglobin which gives them a red colour. They are built for aerobic metabolism and prefer to use fat as a source of energy. These are the marathon runner's muscle fibres.
Type 2A or fast oxidative-glycolytic fibres have a fast contraction speed and a high myosin ATPase activity. They are progressively recruited when additional effort is required, but are still very resistant to fatigue. Their motor neurones show bursts of intermittent activity. These cells are thin (high surface to volume ratio) with a good capillary supply for efficient gas exchange. They are rich in mitochondria and myoglobin which gives them a red colour. They are built for aerobic metabolism and can use either glucose or fats as a source of energy. These are general purpose muscle fibres which give the edge in athletic performance, but they are more expensive to operate than type 1.
Type 2B or fast glycolytic fibres have a fast contraction speed and a high myosin ATPase activity. They are only recruited for brief maximal efforts and are easily fatigued. Their motor neurones transmit occasional bursts of very high frequency impulses. These are large cells with a poor surface to volume ratio and their limited capillary supply slows the delivery of oxygen and removal of waste products. They have few mitochondria and little myoglobin, resulting in a white colour (e.g. chicken breast). They generate ATP by the anaerobic fermentation of glucose to lactic acid. These are sprinter's muscle fibres, no use for sustained performance.
These differences are nicely illustrated by the serial sections from rat diaphragm published by Gauthier and Lowey (1979) J. Cell Biology 81, 10-25. In the figure above, the left hand section was stained for the mitochondrial enzyme succinate dehydrogenase, the centre panel shows direct immunofluorescence against "fast" type myosin, and the right hand section was stained for alkali-stable ATPase activity (i.e. "fast" type myosin). Notice the differences in the fibre diameters, which correlates with their requirements for efficient gas and substrate exchange. Notice also how the mitochondria tend to cluster near the outside of the cells.
Voluntary muscle cells are electrically isolated from each other, and respond only to direct instructions from a particular motor neurone via the motor end plate. They have nicotinic acetylcholine receptors, which are ligand-gated sodium channels concentrated in a specialised region of the muscle sarcolemma beneath the axon terminus. These ion channels respond to acetylcholine (secreted from the nerve) by depolarising the muscle sarcolemma near the motor end plate. The depolarisation triggers voltage-gated sodium channels which spread the excitation over the remainder of the cell.
In cardiac muscle and some types of smooth muscle the cells are in electrical contact through communicating gap junctions. These are important for the orderly spread of excitation through the heart. This starts with the spontaneous depolarisation of the specialised pacemaker cells in the sino-atrial node, spreads via the atria to the atrio-ventricular node and thence to the conducting fibres in the Bundle of His (in the intraventricular septum) and the Purkinje system. These cells finally activate the bulk of the ventricular muscle in the chamber walls, in each case through direct electrical contacts.
Catecholamine hormones such as adrenalin are released during frightening or stressful situations. They increase the force and frequency of cardiac contractions by binding to Beta-1 receptors, which are protein molecules protruding from the outer face of the cardiac sarcolemma. These activate G-proteins within the membrane, which in turn activate the enzyme adenyl cyclase on the inner face of the sarcolemma. Adenyl cyclase produces 3'5' cyclic AMP, which is an important second messenger controlling numerous intra-cellular activities. Cyclic AMP activates protein kinase A which phosphorylates many intracellular enzymes, temporarily modifying their properties.
Cardiac muscle contains muscarinic acetylcholine receptors. These are also linked to adenyl cyclase (via inhibitory G proteins) and to a potassium ion channel in the cardiac sarcolemma. Acetylcholine reduces the levels of cyclic AMP and increases potassium currents, promoting slower, less forceful beats. Many types of smooth muscle also contain gap junctions and muscarinic acetylcholine receptors, but here acetylcholine normally leads to contraction. Depending on the type of smooth muscle, catecholamines may produce either contraction (alpha receptors linked to intracellular calcium stores), or relaxation (beta receptors linked to adenyl cyclase). This relaxation is apparently mediated by the cyclic AMP-dependent phosphorylation and inactivation of the enzyme myosin light chain kinase, which plays a central role in smooth muscle contraction. Vascular smooth muscle redistributes the blood supply during exercise, and visceral smooth muscle empties the gut in stressful or frightening situations. In contrast to all this, the force of contraction in voluntary muscle is unaffected by circulating hormones.Back to the table of contents
The diagram above shows the control of cardiac muscle contraction in greater detail. The Na/K ATPase or sodium pump (1) works continuously, using the energy from ATP to maintain a high K+ concentration inside the cells and a high Na+ concentration in the extracellular fluid (ECF). The cell membrane (sarcolemma) is usually more permeable to potassium ions than to sodium ions, and this gives rise to a membrane potential of about 80mV (inside negative) in relaxed muscle. Calcium ions are also removed from the cytosol into the ECF by an ATP-driven calcium pump (2) in all tissues. Cardiac muscle possesses an additional sodium/calcium exchange protein (3). This export system is driven by the pre-existing sodium ion gradient. The calcium concentration inside resting cells is low, but rises sharply during contractions.
The sarcolemma is very thin (about 6 nm) so the 80mV membrane potential equates to a voltage gradient of about 13,000,000 volts per metre! All membrane components are subject to intense electric fields, and protein conformations are greatly influenced by the membrane potential. "Voltage gated" ion channels will only conduct over a narrow range of membrane potentials, whereas "ligand gated" ion channels (such as the acetylcholine receptor in voluntary muscle) require specific chemical activators.
Contraction in cardiac muscle is triggered by a wave of membrane depolarisation which spreads from neighbouring cells. The change in electric field activates voltage gated sodium channels (4) in the sarcolemma, each of which allows a few hundred positively charged sodium ions to enter the negatively charged cytosol, further reducing the cardiac membrane potential until the whole sarcolemma is depolarised.
The sodium channel undergoes a second conformational change, as a result of which these channels close spontaneously after a few milliseconds in all excitable tissues. In cardiac muscle, but NOT skeletal muscle, slower voltage-gated calcium channels, probably identical with dihydropyridine receptors (5) take over and maintain a positive inward current for several hundred milliseconds (in human ventricle) during the plateau phase of the cardiac action potential. As in nerves and skeletal muscle, the membrane potential in cardiac muscle is eventually restored to its resting value by a delayed efflux of positive potassium ions from the cells.
Dihydropyridine drugs (e.g. verapamil & nifedipine) inhibit calcium entry into heart and reduce blood pressure. About 10% of the calcium needed to activate cardiac contraction enters during each beat from the ECF. This is often described as "trigger calcium". The remainder is released from the sarcoplasmic reticulum through a channel known as the ryanodine receptor (6). Ryanodine receptors are widely distributed in the body, and are present in non-muscle tissues such as brain. The genes coding for this enormous protein (5037 amino acids) have been sequenced. Different tissues have their own specific isoenzymes. The operation of the ryanodine receptor depends in a mysterious way on the flow of calcium ions through the dihydropyridine receptors in cardiac muscle, but not in other muscle types.
Calcium ions from both sources bind to the regulatory protein troponin-C located in the thin filaments (7), leading to a change in filament shape. This allows flexible head groups from the protein myosin in the thick filaments (8) to interact with the protein actin in the thin filaments. A change in myosin conformation causes the thick and thin filaments to slide against each other and hydrolyse ATP, which provides the energy for contraction. Movement and ATP hydrolysis continue until the calcium ions are removed from the cytosol at the end of each contraction. Most of the calcium ions are returned to the sarcoplasmic reticulum by a calcium pump (9) but about 10% leave the cell via proteins (2) and (3) described above. Calcium ions are stored within the sarcoplasmic reticulum loosely bound to a protein, calsequestrin (10).
In cardiac muscle circulating hormones like catecholamines and glucagon bind to specific receptors (11) on the outer surface of the sarcolemma, changing their shape. This change is communicated via G-proteins (12) within the sarcolemma to adenyl cyclase (13) bound to the internal face of the sarcolemma. Several G-proteins are known, some activatory, others inhibitory. They all slowly hydrolyse GTP while working, although it is not clear what advantage this confers on the cell. Adenyl cyclase manufactures 3'5' cyclic AMP, which is continuously destroyed by a phosphodiesterase enzyme. The steady-state concentration of cyclic AMP depends on the balance between synthesis and degradation. Cyclic AMP in turn controls the activity of cyclic AMP-dependent protein kinase. This enzyme phosphorylates several of the proteins involved in the contraction process, and temporarily alters their properties until a protein phosphatase restores the status quo ante by removing the phosphate group.
The sodium pump (1) is activated by phosphorylation, which allows it to handle the increased ion traffic across the sarcolemma when cardiac work output rises.
The dihydropyridine receptor (5) is activated by phosphorylation, increasing calcium entry into the cells. The ryanodine receptor (6) is also activated, increasing the rate of calcium release from the sarcoplasmic reticulum. The troponin-I component in the thin filaments (7) is phosphorylated and this reduces calcium binding to the neighbouring troponin-C. (This may be a defence mechanism preventing tetany in cardiac muscle, which would be rapidly fatal.)
A small protein called phospholamban associated with the sarcoplasmic reticulum calcium pump (9) is phosphorylated, and this accelerates calcium uptake by the S.R. pump. (A fast heart rate requires quick relaxation as well as rapid contraction.)
The enzymes triglyceride lipase (14) and glycogen phosphorylase (15) are activated by phosphorylation. These enzymes catalyse the first steps in the mobilisation of food reserves. They eventually increase the supply of ATP and provide the energy for the anticipated extra work.
These changes take place in a coordinated sequence over many seconds, so that the initial response to adrenalin may be a pounding heart, but both the rate and the force of contraction tend to return to normal when the stimulation is prolonged.
Skeletal muscle can contract in the absence of extracellular calcium, and skeletal S.R, shows depolarisation-induced calcium release In contrast to this, cardiac S.R needs external "trigger calcium" to enter the cells via the dihydropyridine receptors during the plateau phase of each action potential to initiate calcium-induced calcium release (CICR). Cardiac and skeletal ryanodine receptors probably differ in their precise intracellular location. The two genes are on separate chromosomes and show substantial differences. They are also expressed in brain, egg cells and many other tissues, where they regulate calcium release from the smooth endoplasmic reticulum. Dihydropyridine receptors are also present in some smooth muscles. They are blocked by the important drugs verapamil and nifedipine, which reduce the force of cardiac contraction, while maintaining an adequate cardiac output by relaxing vascular smooth muscle and reducing the peripheral vascular resistance.
The system(s) which terminate CICR are far from clear, There must be some mechanism, since otherwise rising cytosolic calcium would lock the S.R. Ca++ release channels in the open state. Perhaps the ryanodine receptor has a built in relaxation time (like the voltage gated sodium channels in the sarcolemma) or perhaps there is a mechanism to sense the emptying of the S.R. The transmembrane protein triadin might provide a link to either measure or modulate calcium binding to the low-affinity binding protein calsequestrin in the lumen of the S.R.
The repeated entry of external calcium ions during the plateau phase of each cardiac action potential requires a cardio-specific calcium export system to stabilise the internal calcium concentration. This is achieved by the electrical exchange of one intracellular Ca++ ion for three extracellular Na+ ions in cardiac muscle. The exchange is assisted by the resting membrane potential. Cardiac glycosides such as ouabain and digitalis (from foxgloves) inhibit the Na/K ATPase, reducing the Na+ gradient across the plasmalemma in all tissues. This specifically increases the force of cardiac (but not skeletal muscle) contraction by interfering with the cardiac Ca++ export system.Back to the table of contents
Muscle tissue accounts for most of an individual's mass and daily energy consumption. Fuel economy is very important, not only for minimising food requirements, but also for reducing unwanted heat production. The different skeletal muscle fibre types are described above: in general the routine tasks are handled by slowly contracting, economical fibres with an fat-based aerobic metabolism, and the more expensive high-speed fibres using carbohydrate fuels are only recruited when the occasion demands. Smooth muscle is particularly economical because it has a low myosin: actin ratio, a low ATPase activity and a much lower contraction speed. It is ideal for sphincters and slow squeezes, and is used for these tasks in preference to striated fibres.
Cardiac muscle contracts quite slowly, but it is used continuously and the total energy consumption is high. It is totally specialised for energy production, and achieves the highest sustained metabolic rates (and the highest arterio-venous oxygen extractions) of any tissue in the body. Mitochondria represent 30-40% of the ventricular mass. This high metabolic rate creates serious diffusion problems within cardiac muscle. There is a high capillary density and the cells are small, with a high surface to volume ratio. The tissue is rich in myoglobin (for oxygen transport) and creatine + creatine phosphate (for energy transport). The organ shows a distinct preference for free fatty acids, ketone bodies and lactate; but requires insulin for efficient glucose uptake and utilisation.Back to the table of contents
Skeletal muscle is the body's major store of amino acids during fasting. These tissues are degraded in an orderly fashion, and release mainly alanine and glutamine into the blood. These amino acids help to maintain blood glucose during fasting through gluconeogenesis in liver, kidney and gut. Skeletal muscles lack a urea cycle, but they are able to transaminate most amino acids and degrade their carbon skeletons as far as Krebs cycle intermediates, such as succinyl-CoA and fumarate. Surplus cycle intermediates are converted via an allosteric NAD-linked "malic" enzyme into pyruvate, which is transaminated to yield alanine. Some amino acids such as serine are deaminated to pyruvate and ammonia, which is de-toxified yielding glutamine. In this way surplus nitrogen is exported from the muscles to the liver, kidney and gut for further processing.Back to the table of contents