01 PHYSIOLOGY
48. Muscle
electrophysiology
What is the resting membrane
potential of a skeletal muscle
cell?
Describe the anatomical
structure of a skeletal muscle.
What are the major components
of the neuromuscular junction?
How is acetylcholine
synthesised and stored within
the nerve terminal?
How does neuromuscular
transmission occur?
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Resting membrane potential for skeletal muscle is –90 mV, nervous tissue is
–70 mV and cardiac muscle is –90 mV.
A skeletal muscle is covered by a connective tissue called the epimysium.
Within the muscle lie thousands of muscle fibres, which are arranged in
bundles or fascicles, surrounded by perimysium. These muscle fibres are
cylindrical, multi-nucleated cells, 10–100 µm in diameter and run along the
entire length of the muscle. They are surrounded by endomysium.
Microscopically, muscle fibres have a striated appearance due to the
presence of numerous myofibrils. The myofibrils are formed by thick (myosin)
and thin (actin) contractile filaments in association with the regulatory
proteins tropomyosin and troponin. These contractile filaments are arranged
within sarcomeres, which form the basic contractile unit of a skeletal muscle.
Neuromuscular transmission occurs across the neuromuscular junction,
which is composed of the α-motor neurone, synaptic cleft and motor end
plate of the muscle fibre.
The end terminals of the motor neurone are unmyelinated, with specialised
sites for the storage and release of acetylcholine (ACh). The motor end
plate of the muscle fibre is deeply folded, with high concentrations of
nicotinic acetylcholine receptors (nAChR) located at the crests of these
folds. Separating these two components is the synaptic cleft, a 20 µm gap
containing acetylcholinesterase.
ACh is synthesised within the axoplasm from choline (obtained from the
diet and liver synthesis) and acetyl coenzyme A (a metabolic by-product)
in a reaction catalysed by choline-O-acetyltransferase. Once formed,
approximately 80% is stored in vesicles available for release. Some of these
vesicles (about 1%) lie at special release sites known as ‘active zones’
and are available for immediate release, while the others form the ‘reserve
pool’, and are ready for transportation to the release site when needed.
A remaining 20% forms a ‘stationary store’ dissolved in the cytoplasm.
When a motor nerve is depolarised, voltage-gated Ca2+ channels open in
the presynaptic membrane, allowing Ca2+ to enter the nerve terminal. This
Ca2+ enables the vesicles to fuse and release their contents, it is believed,
by exocytosis.
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When do extra-junctional
nAChR appear?
Describe the positive feedback
mechanism designed to
increase ACh release.
What is a motor unit?
What is excitation–contraction
coupling?
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MUSCLE ELECTROPHYSIOLOGY
Approximately 100–200 vesicles simultaneously release their ACh, producing
an end-plate potential. When ACh binds to nAChR (pentameric, ligand-
gated ion-channels consisting of 2α, 1β, 1ε and 1δ subunits) the receptor
undergoes a conformational change and the central ion channel opens
sufficiently to allow the passage of cations, predominantly Na+ and K+. This
causes a localised depolarisation of the muscle fibre membrane, which leads
to excitation–contraction coupling. The action of ACh is rapidly terminated by
the presence of acetylcholinesterase within the synaptic cleft.
Extra-junctional nAChR rapidly sprout after denervation and burns injuries.
These receptors are structurally different as the normal ε subunit is
replaced by the fetal γ subunit. They are extremely sensitive to depolarising
neuromuscular blocking agents and the use of these agents can result
in profound hyperkalaemia. This is why suxamethonium is typically
contraindicated in such patients from 24 hours to 2 years after injury. In
contrast, extra-junctional receptors are relatively resistant to non-depolarising
neuromuscular blocking agents and therefore these drugs must be
administered at higher doses.
There are pre-junctional nAChR located on the nerve terminals, which form
a positive feedback mechanism designed to increase the release of ACh
during periods of high activity (e.g. tetanic stimulation). These receptors are
blocked by non-depolarising neuromuscular blocking drugs and this explains
why fade on train-of-four stimulation is observed with these agents.
A motor unit refers to a single motor neurone and all the muscle fibres it
innervates. In muscles involved in fine, precise movement (e.g. eyes and
fingers) the motor units are small and one motor neurone innervates only
a few muscle fibres. This is in sharp contrast to muscles involved in gross,
powerful movement where the motor unit consists of a single neurone
innervating hundreds of fibres (e.g. quadriceps muscle).
This refers to the process by which the electrical activity of muscle
depolarisation results in mechanical changes leading to contraction.
As the action potential travels down the T-tubules, which lie very close to
the sarcoplasmic reticulum, it triggers calcium release channels (i.e. the
ryanodine receptors) on the sarcoplasmic reticulum to open, resulting in an
influx of intracellular Ca2+. This Ca2+ binds onto troponin, bringing about a
conformational change in the troponin–tropomyosin complex, which results
in the exposure of the myosin binding sites on the actin filaments. The
myosin heads bind to actin and perform a ratchet-type movement towards
the centre of the sarcomeres, dubbed ‘the power stroke’. ATP then binds
onto the myosin head, allowing it to detach from the actin. The hydrolysis
of this ATP enables the myosin head to re-orientate itself ready for the next
power stroke. The muscle relaxes when intracellular Ca2+ levels decrease.
Rigor mortis occurs due to the lack of ATP, which prevents the detachment
of the myosin heads from actin and hence the filaments are held in sustained
contraction.
In malignant hyperpyrexia there is a defect in the ryanodine receptor, which
leads to the uncontrolled release of Ca2+ from within the sarcoplasmic
reticulum and hence the sustained muscle contraction and rigidity seen in
this condition.
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