Skeletal Muscle Structure
Skeletal muscle is responsible for converting the electrical impulse from a lower motor neurone that arrives at the neuromuscular junction (NMJ) into a mechanical force by means of contraction. The arrival of the action potential leads to the release of acetyl-choline (ACh) which activates the nicotinic ACh receptor (AChR) in the postsynaptic muscle, which in turn leads to the depolarization of the muscle fibre (see Chapter 16). This produces a calcium influx into the muscle fibre which leads to muscle contraction (see Chapter 21).
Structure of skeletal muscle
Skeletal muscle is composed of groups of muscle fibres which are long, multinucleated cells. These fibres contain myofibrils, which in turn are made up of thick and thin filaments that overlap to some extent giving this type of muscle its striated appearance. The myofibrils are bounded by the sarcolemma, which invaginates between the myofibrils in the form of transverse or T-tubules. This structure is separate from the sarcoplasmic reticulum (SR), which envelops the myofibrils and is important as an intracellular store of Ca2+. The sarcolemma is a complex structure and abnormalities in its membrane components have recently been found to underlie some forms of inherited muscular dystrophies.
The thick filament is composed of myosin and lies at the centre of the sarcomere.
• Myosin is composed of two heavy chains that are form by the light and heavy meromyosin proteins (LMM and HMM, respectively).
• The HMM portion contains S1 and S2 subfragments.
• The S1 fragment consists of two heads and associated with each of these heads are two light chains.
• The light chain found at the tip of the S1 head is termed non- essential and is responsible for breaking down adenosine triphos- phate (ATP) at the end of the power stroke of crossbridge formation.
• The remaining essential light chain is attached at the point where the S1 head swings out towards the actin and is important in the process of myosin head movement.
• By virtue of the properties of LMM, myosin filaments spontaneously pack together so that the S1 heads are on the outside towards the actin filaments. The S1 heads therefore form the major part of the crossbridge with the actin.
Thin filaments are composed of F-actin, tropomyosin and troponin. Troponin is itself composed of three subunits (troponin-I, -C and -T).
• These three components of the troponin complex all subserve different functions but as a whole they regulate muscle contraction by holding the tropomyosin in position so that it physically blocks the S1 head of the myosin from binding to the actin.
• The depolarization of the muscle leads to a calcium influx which then binds to troponin, producing a conformational change in the thin filament such that the tropomyosin shifts off the binding site for myosin on actin.
• Thus, tropomyosin and troponin regulate muscle contraction by a process of stearic block. In some muscles in other animals, the regulation of the interaction between actin and myosin lies with the myosin associated light chains.
At the point of overlap of these two sets of filaments is found the triad structure of a T-tubule, linked to two terminal cisternae of SR by foot processes.
Disorders of structural proteins in skeletal muscle – the muscular dystrophies
There are many disorders, including:
• Disorders of excitability through mutations in the ion channels (see Chapter 14).
• Inflammation within the muscle (see Chapter 62).
• Abnormalities in the structural proteins.
These latter conditions underlie many of the inherited muscular dystrophies, of which the best characterized are Duchenne’s and the limb girdle muscular dystrophies.
Duchenne’s muscular dystrophy (DMD) is an X-linked disorder in which there is a deletion of the gene coding for the structural protein dystrophin, with the milder form of the disease (Becker’s muscular dystrophy) having a reduced amount of this same protein. Patients with DMD typically present early in life with clumsiness and difficulty in walking, with an associated wasting of the proximal limb muscles and pseudohypertrophy of the calf muscles. As the disease progresses the patient becomes increasingly disabled, with the development of cardiac and other abnormalities which lead to death, typically in the third decade. Characteristically, these patients have a raised creatine kinase (a marker of muscle damage) as the muscles in these patients are prone to necrosis as a result of the absence of dystrophin. This protein lies beneath the sarcolemma of skeletal (as well as smooth and cardiac) muscle and provides stability and flexibility to the muscle membrane, such that when absent the membrane can be easily disrupted. This allows entry of large quantities of Ca2+, which precipitates necrosis by excessive activation of proteases.
The limb girdle muscular dystrophies (LGMD), in contrast, can present at any age with progressive weakness of the proximal limb muscles and a raised creatine kinase. The condition can be inher- ited in a number of different ways, and recently the autosomal recessive forms of this condition have been found to contain abnormalities in the dystrophin associated glycoproteins, adhalin and the sarcoglycan complex. These proteins link the intracellular dystrophin with components of the extracellular matrix and so are important in maintaining the integrity of the sarcolemma.
There is also some evidence that in myasthenia gravis (see Chapter 16) antibodies can also be found against some of these structural proteins such as the ryanodine receptor and titin.
Disorders with inflammation of skeletal muscle – the myositides
In a number of disorders there is selective inflammation in skeletal muscle, including:
• Inflammation for unknown reasons with a predominant T-cell infiltrate (polymyositis);
• Inflammation with a predominant B-cell mediated process (dermatomyositis) that can be paraneoplastic in nature;
• A degenerative disorder that has a significant secondary inflammatory response (inclusion body myositis).
The former two conditions tend to respond to immunotherapy, while inclusion body myositis does not. In all cases the inflammation damages the muscle, causing weakness often with pain, and a raised serum creatine kinase.