Pathophysiology of Skeletal Muscle

Question 1

What is malignant hyperthermia?

Answer 1

MH is a genetic disorder in which patients are susceptible to a dangerous hyperthermic state triggered by volatile anaesthetics.
The cause is a mutation in the Ryanodine receptor, which as a result releases calcium indiscriminately, leading to over-activity of SERCA. This high ATP-ase activity leads to enormous heat generation, which can cause destruction of the muscle tissue (rhabdomyolysis), and consequent multi-organ failure

Question 2

What is myasthenia gravis?

Answer 2

MG is an autoimmune disorder in which auto-antibodies are made against the nicotinic ACh receptor, reducing AChR numbers, so transmission of neuromuscular junction signalling is attenuated.
This results in proximal muscle weakness and muscle fatigue.

Question 3

List some common symptoms for myasthenia gravis.

Answer 3

Proximal muscle weakness, which includes their being easily fatigued.
The most common symptoms are eyelid and eye muscle symptoms (e.g. ptosis, partial closure of upper lid, and diplopia, double vision due to lack of eye convergence).

Question 4

Atropine is an anti-cholinergic agent. Why doesn’t the drug atropine lead to symptoms of myasthenia gravis?

Answer 4

The symptoms of myasthenia gravis arise from failure of cholinergic activity in the neuromuscular junction

Atropine block metabotropic cholinergic receptors
Atropine does not affect the nicotinic receptors at the Neuromuscular junction

Thus, atropine is acting at completely different sites/receptors than the nicotinic problems arising from MG

Question 5

What are some treatments for myasthenia gravis.

Answer 5

Acetylcholine-esterase inhibitors (eg pyridostigmine).
It increases signalling of ACh by increasing the amount of ACh in the synapse during endogenous neural activity

Reduction of immune activity (thymectomy, or corticosteroids, but these have many adverse effects)

Question 6

How does rigor mortis occur (in terms of excitation-contraction coupling)?

Answer 6

ATP is depleted after death
SERCA (Ca2+ pump) ceases to resequester Ca2+
causing increase in Cytosolic Ca2+
Ca2+ allows crossbridge cycle contraction
Until ATP & creatine-P runs out
W/o ATP –> myosin stops just after power stroke
With myosin still bound to actin
Thin and thick filaments are bound together, and sarcomere cannot expand
Rigor mortis ends when muscle proteins degrade ~ 3 days after death

Question 7

Name two plasma markers from skeletal muscle that could be used to indicate rhabdomyolysis – and what does each one do normally?

Answer 7

Total (CK-MM) – allows buffering of high energy phosphate bonds between ATP and creatine
Plasma K+. Normally K+ is 50X higher intracellularly than extracellularly (because of the Na/K pump), so if large number of myocytes release their intracellular contents, plasma K+ may increase.
Myoglobin – stores O2 in myocytes. Myoglobinuria is a sign suggesting rhabdomyolysis. Plasma myoglobin increases after skeletal or cardiac muscle damage

Question 8

Why does the number of muscle fibres not increase (or increases by very little) during the course of life?

Answer 8

Skeletal muscle does not (in general) proliferate; it grows by hypertrophy.
Proliferation via mitosis tends to be quite difficult in multinucleate cells
Because there cannot be a mitotic spindle

Question 9

List the changes in fibre type ratio that accompany muscle atrophy during extensive bed rest.

Answer 9

An increase in type IIa (non-oxidative, fast twitch) fibres with respect to type I (oxidative, slow twitch)
Diminution of all fibre types, (but weight-bearing muscles (with mostly type I fibres) are most affected)

Question 10

What are features of Type I skeletal muscle fibres (7)

Answer 10

Slow-twitch
More aerobic
More myoglobin
Slower calcium resequest
More fatigue resistance
Thinner diameter
Darker in colour

Question 11

What are features of Type IIb skeletal muscle fibres (7)

Answer 11

Fast-twitch
More glycolytic /anaerobic
Less myoglobin
Faster calcium resequest
Fatigue sensitive
Larger diameter
Lighter in colour

Question 12

List the adaptations that skeletal muscle makes as a result of exercise. (3)

Answer 12

Size (increase, hypertrophy)
Capillarisation / Vascularisation (increase)
Fibre type transitions

Question 13

What are the general processes that tissue would undergo when it is either becoming larger or smaller?

Answer 13

Hypertrophy/ Atrophy

Necrosis/ Proliferation

Question 14

What are the processes by which hypertrophy occurs? (4)

Answer 14

Synthesis of myofilaments
Addition of sarcomeres
Satellite cell activation
Vascularisation

Question 15

What are the main effects in muscles as a result of endurance exercise? (4)

Answer 15

Mainly, increase in blood supply (vascularisation).
Increase in mitochondria.
Increase in oxidative enzymes.
To a smaller extent, fibre diameter changes, fibre types may change.

Question 16

What are the main muscular effects of non-endurance exercise? (2)

Answer 16

Increase in Type IIx fibre size
Increased number of sarcomeres and myofilaments

To a lesser extent, conversion of Type IIa fibres to Type IIx fibres

Question 17

Describe the difference between a sprain and a strain.

Answer 17

A sprain is an injury to connective tissues, such as ligaments. A strain is an injury to muscles, such as through overuse.

An acute sprain may be treated most likely with ice, a strain may be treated BEFORE exercise with heat.

Question 18

What is the effect of space flight on skeletal muscle?

Answer 18

A decrease in muscle mass though atrophy, predominantly in weight bearing muscles.
To a lesser extent, transition of some Type I fibres to Type IIa or Type IIx fibres.

Question 19

What would you do to minimise with muscle atrophy due to bed rest?

Answer 19

Treat by resuming minor activity early.

Add physiotherapy to prevent contractures.

Question 20

What is a contracture?

Answer 20

It is shortening of a myofibre (muscle) by removal of sarcomeres. This results in joints that cannot extend fully.

Question 21

Describe the histological appearance of skeletal muscle cells.

Answer 21

Long, cylindrical, multinucleate, peripheral nuclei. Extensive striation.

Question 22

What are myosatellite cells?

Answer 22

They are small cells that abut myofibres that are important in regeneration and skeletal muscle growth. They are generally quiescent, but they are activated upon inflammation and degeneration (damage of muscle). Once activated, these cells proliferate and differentiate on extant fibres, helping to repair them.

Question 23

Describe the differences between fasciculations and fibrillations.

Answer 23

Both are quite small, involuntary muscle twitches.

Fasciculations are neurogenic and therefore affect an entire motor unit (ie multiple myofibres); they can be seen as brief ripples beneath the skin .

Fibrillations are myogenic; they affect only single myofibres. Fibrillations cannot be seen visibly, but are detected by electromyography. They are often associated with denervated muscle fibres.

Question 24

Name 5 causes of rhabdomyolysis.

Answer 24

Crush injury (e.g. after earthquakes, car crashes)
Adverse effects of statins or fibrates (or other toxins)
Malignant hyperthermia (& other genetic diseases of muscle)
Hyperthermia
Diabetic ketoacidosis

Question 25

When diagnosing a patient with rhabdomyolysis, what signs and symptoms would you expect to find? (7)

Answer 25

Muscle pains
(Potentially) vomiting and confusion
decrease in urine production
Urine may be tea coloured – myoglobin in plasma & urine
Potential for kidney failure
Possibly electrolyte changes, including hyperkalemia
Increases in serum creatine phosphokinase

Question 26

Explain the mechanism of spinal muscular atrophy.

Answer 26

Death of lower motor neurons due to lack of survival factors in the anterior horn of the spine.
Leads to muscle atrophy, hypotonia and muscle weakness.

Question 27

What is “Fibre type grouping” - cause?

Answer 27

When the same tissue type groups together instead of being evenly distributed throughout the muscle
This results from “spinal muscle atrophy” and from chronic denervating diseases (that have denervation-renervation cycles).

Question 28

What is the mechanism of fibre type grouping in spinal muscular atrophy?

Answer 28

Cycles of denervation and collateral reinnervation mean that surviving axons innervate denervated fibres. Thus, all fibres in a region may be innervated by the same lower motor neuron.
This motor neuron determines fibre type, so all fibres next to one another become the same fibre type.

Question 29

How is malignant hyperthermia treated?

Answer 29

Patients who begin the process can be treated with dantrolene sodium, which inhibits the ryanodine in receptor.

Question 30

Explain the mechanism of Duchenne muscular dystrophy.

Answer 30

A mutation in a dystrophin protein (x-linked) means that there is progressive loss of muscle tissue due to rounds of degeneration and regeneration of muscle fibres.
These are replaced by fibrofatty tissue, resulting in muscle wasting and muscle weakness.