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Basically, in response to a physiological stimulus, muscles transduce an electrochemical signal to a mechanical response which results in the generation of force. The human body contains three fundamental types of muscle: skeletal, smooth and cardiac. These three types of muscles are unique in their physiological roles and subsequently, they differ in terms of anatomical structure, contractile action and metabolism. However, what the muscle cells share in common is that a rise in cytosolic calcium concentration is necessary for contraction. This paper will focus on the differences in cellular physiology and function between skeletal muscle and smooth muscle.
Skeletal muscle must be voluntarily controlled and is innervated by somatic efferent neurons originating from the motor cortices of the brain. These neurons terminate at the neuromuscular junction, a specialised synapse where the post-synaptic membrane is the plasma membrane of the skeletal muscle fibre (sarcolemma). A single muscle cell is associated with a single neuron, but one neuron can innervate several muscle fibres in what is called a motor unit. At a neuromuscular junction, the neuron divides into a tree-like formation of unmyelinated nerve processes called terminal arborisations, with bulb-shaped boutons at the end of each process. The boutons are in contact with the post-synaptic muscle membrane, which contains folds that greatly increase the membrane surface area and hence the number of acetylcholine receptors. The terminal boutons release acetylcholine, which binds to nicotinic acetylcholine receptors on ion channels. Since nicotinic acetylcholine receptors are non-selective cation channels, with binding, Na+, K+ and Ca2+ enter the cell. The increase in Na+ conductance raises the membrane potential in the end-plate region in what is called an excitatory post-synaptic end-plate potential. When this end-plate potential reaches a certain depolarisation threshold (around -65 mV), voltage-gated ion channels in the post-synaptic membrane open and a sharp depolarisation results. An action potential then propagates in the muscle membrane, eventually leading to contraction.
Skeletal muscle cells are multi-nucleated, and each fibre extends along the length of the entire muscle. Each muscle fibre is composed of a dense, parallel array of cylindrical myofibrils, which make up 80% of the volume of a muscle fibre. A myofibril is approximately 1 µm in diameter, and also runs along the entire length of the muscle. A myofibril is further comprised of repeating units of sarcomeres, and each sarcomere contains repeating myofilaments. There are two types of myofilaments which interlace in an extremely organised fashion: a thick filament comprised of mostly myosin, and a thin filament composed of mainly actin. Because of this organised arrangement of thick and thin filament in a sarcomere, myofibrils exhibit a striped appearance and hence skeletal muscle is termed 'striated muscle'. The ratio of thick to thin filaments is approximately 1 to 2, and a single muscle fibre can contain up to 16 billion thick filaments and 32 billion thin filaments.
Thick and thin filaments are arranged in such a fashion that they overlap at certain intervals. Thin filaments are attached at the Z disk. The interval in which the Z disk is at the centre, and where thin filaments do not overlap with thick filaments is termed the I band, named because this region is isotropic to polarised light. The thick filaments span what is termed the A band, named because the region is anisotropic to polarised light due to overlap between thin and thick filaments at the ends of the A band. The interval in which only thick filaments are present in a resting muscle fibre is called the H zone, and at its centre, the M line. When a muscle contracts, the H zone and I band shorten as thick and thin filaments slide over each other, with no change to the length of thick or thin filament.
Thick filaments are bipolar assemblies of protein polymers that are primarily composed of myosin-II molecules. Myosin-II is a hexamer (strictly, a double trimer) consisting of two intertwined heavy chains, two regulatory light chains and two essential (alkali) light chains. Each of the heavy chains has a head region, also called an S1 fragment, a hinge region connected to the heads, and a tail region. The hinge and tail regions are α-helices. The myosin heads contain a binding site for actin and a binding site for ATP, and they also form a complex with the two myosin light chains. The essential light chain is involved in stabilisation of the head region, and the regulatory light chain regulates myosin ATPase activity. This regulatory light chain itself is regulated by Ca2+-dependent and Ca2+-independent kinases. Thick filaments are positioned in between the Z disks and are attached to the Z disks via titin (also known as connectin). Titin is the largest identified single polypeptide to date, and a single titin molecule spans approximately half the sarcomere. It is an elastic protein which functions as a 'molecular spring', keeping the thick filaments positioned in the middle of the sarcomere and aiding the muscle fibre's recovery after being stretched. Titin interacts with many other regulatory sarcomeric proteins, serving as a template protein and sarcomeric stabiliser (Clark et al. 2002).
Thin filament is composed of actin, tropomyosin and troponin. The actin is in the form of a double-stranded α-helical polymer, and each helical turn of a single strand of F-actin is composed of 13 individual actin monomers. Actin is attached with its plus end at the Z disk, and its minus end extends toward the M line. The Z disk is a complex protein network composed of mainly α-actinin, but also consisting of numerous α-actinin-associated proteins and other Z disk associated proteins such as obscurin and filamin. Actin is capped on the Z disk by CapZ and at its minus end by tropomodulin. The capping acts to prevent depolymerisation. The length of the thin filament is determined by a very large and inextensible actin-binding protein, nebulin, which acts as a 'molecular ruler' (Clark et al. 2002). Overall, the thin filament is extremely stable. Tropomyosin binds along the groove of the actin helix; it is an elongated molecule composed of two α-helices and extends the length of the actin polymer. Tropomyosin covers the myosin head binding sites on the actin polymer until contraction is stimulated by Ca2+ binding. Troponin is a heterodimer of troponin T, troponin C and troponin I, and it is bound at intervals along the actin polymer. Troponin T binds to tropomyosin, troponin C binds Ca2+, and troponin I binds to actin.
Regardless of the type of muscle, the common trigger for muscle contraction is a rise in cytosolic Ca2+ concentration, and the length of time during which cytosolic Ca2+ remains elevated determines the duration of contraction. The process of electrical signalling leading to the rise in Ca2+ concentration, eventually leading to contraction is referred to as 'excitation-contraction coupling'. Skeletal muscle sarcolemma contains specialised extensions deep into the muscle cell in the form of radially projecting transverse tubules (T tubules). T tubules surround each myofibril and penetrate the muscle at the junctions of the A and I bands in each sarcomere. Along the T tubules, two terminal cisternae of the sarcoplasmic reticulum are in contact, forming what is referred to as a triad. The sarcoplasmic reticulum serves as the store of intracellular Ca2+. In skeletal muscle, as an action potential travels down the sarcolemma, it traverses down the T tubules and eventually depolarises the triad region. In this region, the membranes of the T tubules contain heteropentameric L-type (voltage-dependent) Ca2+ channels clustered in groups of four (a tetrad). The membranes of the terminal cisternae contain homotetrameric Ca2+ release channels called ryanodine receptors. Each of the four subunits of the ryanodine receptor contains a large 'foot' which projects into the cytosol, and each of the four feet of the ryanodine receptor is coupled with an L-type Ca2+ channel within the tetrad. Depolarisation of the T tubule membrane causes the L-type Ca2+ channels to change conformation, which induces a parallel conformational change in the ryanodine receptor. It is believed that the L-type Ca2+ channels and the ryanodine receptor then become mechanically coupled. Ca2+ stored in the sarcoplasmic reticulum exits via the ryanodine receptors and enters the cytosol. The conformational change of the L-type Ca2+ channels has a second effect in allowing Ca2+ to directly enter the cytosol, causing local elevations in intracellular Ca2+. This local Ca2+ influx can also activate ryanodine receptors in a mechanism termed Ca2+-induced Ca2+ release. However, this mechanism is negligible in skeletal muscle due to stored Ca2+ recycling in the sarcoplasmic reticulum, but rather it is more important in cardiac muscle.
The rise in cytosolic Ca2+ concentration triggers and maintains contraction, and a following decrease in cytosolic Ca2+ inhibits contraction and causes the muscle to relax. Ca2+ does not interact directly with contracting proteins, but rather it regulates contraction through regulatory proteins. In the absence of Ca2+, regulatory proteins inhibit the interaction between thick and thin filaments, preventing contraction. When Ca2+ binds to these regulatory proteins, the inhibitor of contraction is taken away.
In skeletal muscle, Ca2+ binds to troponin C to release inhibition of cross-bridge cycling. Each troponin C has two high-affinity and two low-affinity binding sites for Ca2+. Ca2+ binding to the low-affinity sites induces a conformational change in the troponin complex, where the C terminus of the troponin I moves away from the actin/tropomyosin filament, thus allowing movement of the tropomyosin chain. Secondly, troponin T moves to push tropomyosin into the groove of the actin α-helix, uncovering the myosin binding sites on actin. Cross-bridge cycling is powered by ATP. ATP binds to the heads of the myosin heavy chain, and acts to reduce the affinity of myosin for actin, hence releasing the myosin head from actin. As ATP hydrolyses, an inorganic phosphate (Pi) is released and ADP remains. These products are retained on the myosin head. As a result of hydrolysis, the myosin hinge region moves the heads to a 90 degree angle relative to the thick filaments. As a consequence of this movement, the myosin head is now lined up with a new actin monomer two monomers down from the previous one. In the two previous states, the muscle is fully relaxed. If Ca2+ is present and the myosin binding sites on actin is exposed, cross-bridge formation occurs as the myosin head binds to the actin monomer. This is because the myosin-ADP-Pi complex has a higher affinity for actin that myosin-ATP. Striated muscle control cross-bridge cycling at this step via tropomyosin. Release of Pi from the complex triggers what is known as the power stroke, a conformational change in which the myosin head bends from the 90 degree angle to a ~45 degree angle, and in the process pushing the actin filament along, thereby producing motion and force. Lastly, ADP dissociates from the complex and the myosin head is left attached to the actin monomer at the same 45 degree angle. The system remains in this state indefinitely until another ATP binds to the myosin head. This is evident after death in a phenomenon termed rigor mortis, where muscles become rigid and stiff due to the lack of ATP production.
Each cross-bridge cycle requires one ATP molecule, so it is easy to imagine the vast quantities of ATP needed for muscle contraction. In skeletal muscle, the entire cellular store of ATP is used up in a few seconds of continual maximal contraction. Thus, muscle cells are required to resynthesise ATP from ADP at a rate comparable to the ATP consumption rate. In skeletal muscle, phosphocreatine stores some energy in its phosphate bond. Creatine phosphotransferase transfers the phosphate on phosphocreatine to ADP, thereby phosphorylating ADP to ATP. While high in energy content, phosphocreatine is still only sufficient in replenishing ATP in contracted muscle for several seconds. The most abundant energy store in skeletal muscle is glycogen, which can be degraded to glucose-6-phosphate, then to pyruvate to produce ATP. Pyruvate is further utilised in oxidative metabolism to produce large quantities of ATP, which in the long term is the primary mechanism for ATP production. However, in the short term, the rate of ATP generation by this path is limited by oxygen delivery to muscle tissue. Muscle cells employ glycolysis or anaerobic metabolism instead, where pyruvate is converted to lactate independent of oxygen to release ATP.
After the stimulus for contraction has been taken away, termination of muscular contraction occurs when Ca2+ is taken out of the cytosol and back into the sarcoplasmic reticulum. Ca2+ reuptake is aided by sarcoplasmic and endoplasmic reticulum calcium ATPase (SERCA). The SERCA pump hydrolyses one ATP molecule to exchange two Ca2+ ions for one H+ ion. High concentration of Ca2+ within the SR lumen is known to inhibit SR pump activity, so Ca2+-binding proteins within the SR lumen are employed to delay this inhibition. Two types of Ca2+-binding proteins exist in muscle: calreticulin is present in all muscles but is particularly abundant in smooth muscle, and calsequestrin, which is the principal Ca2+-binding protein of skeletal muscle. These proteins can bind up to 50 Ca2+ ions per molecule, hence significantly increasing the Ca2+ storing capacity of the SR. In skeletal muscle, calsequestrin is highly localised at the region of the SR immediately adjacent to the triad. Calsequestrin forms a complex with the ryanodine receptor and two other triad proteins, junctin and triadin. It has been hypothesised that excitation-contraction coupling promotes Ca2+ release from calsequestrin, which in turn facilitates the coupling, acting as a buffer of Ca2+ within the SR lumen.
Skeletal muscle is not uniform throughout the body; it is extremely diverse depending on the location and functions of the muscle fibre, and varies with different demands for speed, strength and fatigability. Skeletal muscle can be classified into two broad types: slow-twitch and fast-twitch fibres. Slow-twitch fibres