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.
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Myosin is
composed of two heavy chains that are form by the light and heavy meromyosin
proteins (LMM and HMM, respectively).
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The HMM
portion contains S1 and S2 subfragments.
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The S1
fragment consists of two heads and associated with each of these heads are two
light chains.
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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.
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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.
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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.
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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).
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Inflammation
within the muscle (see Chapter 62).
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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);
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Inflammation
with a predominant B-cell mediated process (dermatomyositis) that can be
paraneoplastic in nature;
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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.
