Skeletal Muscle Contraction
Summary of sequence of events
in the contraction of muscle
•
The
arrival of the action potential at the neuromuscular junction (NMJ) leads to an
influx of Ca2+ and the release of vesicles containing acetylcholine
(ACh).
•
ACh then
binds to the nicotinic ACh receptor (AChR) on the muscle fibre leading to its
depolarization.
•
Ca2+
is then released from the sarcoplasmic reticulum (SR) of the muscle.
• Ca2+
release leads to the removal of the blocking calcium-binding protein complex of
tropomyosin and troponin from actin, the main component of
the thin filament.
•
Removal of
this stearic block allows myosin, the major component of the thick
filaments, to bind to actin via a cross-bridge.
•
The fibres
are then pulled past each other; the cross-bridge between the two fibres is broken at the end of
this power stroke by the hydrolysis of adenosine triphosphate (ATP).
The cycle of cross-bridge formation
and breakage can then be repeated and the muscle contracts in a ratchet-like
fashion.
Sequence of events in the
contraction of muscle
• Stage 1
In the resting
state the troponin complex holds the tropomyosin in such a position that it
blocks myosin from binding to actin (stearic block).
• Stage 2
The arrival of an action potential
at the NMJ causes a postsynaptic action potential to be initiated, which is
propagated down the specialized invagination of the muscle membrane known as
the transverse tubule (T-tubule). This T-tubule conducts the
action potential down into the muscle, so that all the muscle fibres can be
activated. It lies adjacent to the terminal cisternae of the SR in a structure
known as a triad, i.e. a T-tubule lies between two terminal cisternae of
the SR (muscle equivalent of smooth endoplasmic reticulum) which contain high
concentrations of Ca2+.
The T-tubules are linked to the SR
by foot processes, which are part of a calcium ion channel. The arrival of the
action potential at the triad leads to the release of Ca2+ from the
terminal cisternae, by a process of mechanical coupling. The action potential
opens a common Ca2+ ion channel between the T-tubule and SR, which
then allows Ca2+ to influx down its electrochemical gradient towards
the myofibrils. The Ca2+ then binds to the troponin complex and this
leads to a rearrangement of the tropomyosin so that the myosin head can now
bind to the actin, forming a cross- link or cross-bridge.
• Stage 3
Once the myosin has bound to the
actin there is a delay before tension develops in the cross-bridge. The tension
pulls and rotates the actin past the myosin and this causes the muscle to
contract. The cross-bridge at the end of this power stroke detaches the myosin from actin with hydrolysis of ATP, a
process that is also calcium
dependent.
The whole cycle can then be
repeated. The process of cross- bridge formation with filament movement is
called the sliding filament hypothesis of muscle contraction, as the two
filaments slide past each other in a ratchet-like fashion as the cycle repeats.
The Ca2+ released by the terminal cisternae of the SR, allowing the
process of cross-bridge formation and breakage, is actively taken back up into
this structure by a specific Ca2+ pump.
Disorders of muscle contraction
Diseases of the muscles, which
disrupt their anatomy, will lead to weakness as a consequence of a
disorganization of contractile proteins. However, there are some disorders in
which there is a disruption of the contractile process itself and examples of
this are the rare periodic paralyses and malignant
hyperthermia/ hyperpyrexia. In this latter condition there is an
abnormality in the ryanodine receptor which is part of the protein complex
linking the T-tubule to the SR. This leads, under certain circumstances such as
general anaesthesia, to sustained depolarization, contraction and necrosis of
muscles resulting in an increase in body temperature and multiorgan
dysfunction. In contrast, the periodic paralyses involve
abnormalities in the ion channels that can lead to prolonged inexcitability of
muscles, which thus become weak and paralysed. These are rare disorders and
respiratory muscles are not involved; the paralysis can be provoked by a number
of insults such as exercise or high carbohydrate meals.
It is also important to remember
that disorders of muscle con- traction occur as a consequence of abnormalities
at the NMJ (see Chapter 16), as well as with some inborn errors of metabolism.
These latter metabolic myopathies involve inherited defects in
either carbohydrate or lipid metabolism, which lead to either episodic exercise-induced
symptoms or chronic progressive weakness.
