Pathophysiology of skeletal muscle

Question 1

Muscle plasticity: adaptations

Answer 1

Structural
- e.g. size, capillarisation

Contractile properties
- e.g. fibre type transitions

Adaptability occurs from embryogenesis into maturity

Question 2

Capillarisation

Answer 2

The formation and development of a network of capillaries to a part of the body

Often occurs in muscle in response to long term exercise

Also occurs in cancerous tissue

Question 3

Structural adaptation

Answer 3

Total number of muscle fibres fixed at birth
- e.g. 200,000 biceps brachii

Muscle growth: hypertrophy

• synthesis of myofilaments
• addition of sarcomeres
• satellite cell activation
• angiogenesis and vascularisation

Some muscles enlarge by between 15-50%

Question 4

Effect of endurance exercise

Answer 4

Increased

• fibre diameter
• blood supply
• mitochondrial content

Will express increase in oxidative enzymes

Fibres become slower

Gradual transformation from type IIX to type IIA

Question 5

Non-endurance exercise

Answer 5

Conversion to type IIX

• from type IIA
• greater muscle force and strength

Increase in type IIX fibre size due to increase in number of sarcomeres and myofilaments

Results in much larger muscles

Increase in power

Question 6

Ice

Answer 6

Reduces swelling
- by reducing perfusion

After an acute injury
- sprain

After exercise in overuse injury

Question 7

Heat

Answer 7

To relax and loosen tissues

Use before activities that irritate chronic injuries
- strain

Increases blood flow

Question 8

Sprain

Answer 8

Injury to a ligament

Question 9

Strain

Answer 9

Injury to muscle or a tendon

Question 10

Aspirin

Answer 10

NSAID, reduces pain, reduces inflammation

Used for

• chronic diseases (osteoarthritis)
• sports injuries

Mechanism

• inhibits COX
• reduces synthesis of prostaglandins
• part of arachidonic acid pathway

Side effects

• stomach bleeding
• ulcers

Question 11

Anabolic effects of testosterone

Answer 11

Increases protein synthesis

Decreases catabolism by opposing cortisol and glucocorticoids

Reduces fat: increases BMR, increases differentiation to muscle

Question 12

Anabolic steroid abuse

Answer 12

Used to increase muscle size and strength

Large doses required- leads to damaging side effects (kidney, liver, heart, mood changes)

Male- testes atrophy, sterility, baldness

Female- breast/ uterus atrophy, menstrual changes, facial hair, deepening of voice

Question 13

Effect of spaceflight

Answer 13

Humans- transition of type I fibres to type IIA/X fibres

Decrease relative muscle mass- all muscles undergo some atrophy, but predominantly weight bearing muscles

Question 14

Effect of bed rest

Answer 14

Transition of type I fibres to type IIA

Weight bearing muscle atrophy

• decrease muscle protein synthesis
• myofibrillar breakdown
• decrease strength
• loss of type I fibres

Treat by resuming minor activity early

Question 15

Contracture

Answer 15

If limb immobilised for long periods

• process of growth is reversed
• sarcomeres are removed in series from myofibrils
• resulting in shortening of muscle called a contracture

Patients with paralysed limbs must have physical therapy to prevent contractures occurring

Question 16

Skeletal muscle cells are multinucleate

Answer 16

They develop as myoblasts

• which are mononucleate
• then the myoblasts fuse

The nuclei are peripheral

The multinucleate cells do not divide
- mitosis with multiple nuclei is usually impossible

Skeletal fibres are enlarged by

• fibre enlargement
• increased vascularisation

Question 17

Muscle regeneration

Answer 17

During inflammation and degeneration of damaged muscle tissue

Previous quiscent myogenic cells, called satellite cells, are activated

• they proliferate, differentiate and fuse onto extant fibres
• they contribute to forming multinucleate myofibres

Question 18

Myosatellite cells

Answer 18

Progenitor cells in muscle
- also called satellite cells

Essential for regeneration and growth

Most are quiescent
- activated by mechanical strain

Activation -> proliferation and differentiation

Question 19

Myalgia

Answer 19

Muscle pain

Causes: injury, overuse, infections, auto-immune

Can be associated with rhabdomyolysis

Question 20

Myopathy

Answer 20

Muscular weakness due to muscular muscle fibre dysfunction

• cf. meuropathy and neurogenic disorders
• failure to contract cause possibly muscle or nerve

Systemic vs familial

Dystrophies: familial, progressive

• stuck in degeneration- regeneration cycle
• eventually regenerative ability is lost

Question 21

Paresis

Answer 21

Weakness of voluntary movement, or partial loss of voluntary movement or impaired movement

Usually referring to a limb

From greek ‘to let fall’

Question 22

Fasciculations

Answer 22

Involuntary visible twitches in single motor units

Commonly occur in lower motor neuron diseases such as damage to anterior horn cell bodies characteristic of ALS or polio

Clinically appear as brief ripples under the skin

Question 23

Fibrillations

Answer 23

Involuntary spontaneous contractions of individual muscle fibres invisible to the eye

Identifiable by electromyography

Question 24

Rhabdomyolysis

Answer 24

Rapid breakdown of skeletal muscle
- not cardiac muscle, not myocardial infarct

Risk of kidney failure

• cellular proteins released into blood can clog renal glomeruli
• urine is tea coloured, no urine produced 12 hours after injury
• leads to electrolyte changes: hyperkalaemia

Question 25

Treatment of rhabdomyolysis

Answer 25

Intravenous fluids Possibly haemodialysis

Question 26

Causes of rhabdomyolysis

Answer 26

Trauma: crush injury Drugs - adverse effects of statins or fibrates Hyperthermia Ischaemia to the skeletal muscle - compartment syndrome - thrombosis

Question 27

Symptoms and signs of rhabdomyolysis

Answer 27

Muscle pains Vomiting and confusion Dark urine

Question 28

Serum levels CPK: diagnostic

Answer 28

Creatine phosphokinase - CK or CPK abbreviations used interchangeably - the enzyme, not creatine phosphate Distinct forms of CPK not found in different tissues Skeletal muscle CPK isoform is CK-MM Cardiac muscle CPK isoform is CK-MB When tissue damage and cells lyse there is a relase of tissue specific CK from cells into blood Elevations in CK-MM occur after skeletal muscle trauma or necrosis

Question 29

Myoglobin: diagnostic

Answer 29

Buffers O2 Protein and haem group Tea coloured In plasma indicated rhabdomyolysis or MI - can lead to renal failure - urine tested for myoglobin Diagnostic: hyperkalaemia - when muscle cells lyse - they release K+ - this increases serum K+

Question 30

Myasthenia gravis

Answer 30

Progressive muscle weakness and fatiguability - often starts with eye muscle Caused by depletion of nAChR Arises as the immune system inappropriately produces auto-antibodies against nAChR Less depolarisation of muscle fibres - many fibres do not reach threshold Repeated stimulation -> neuromuscular fatigue Symptoms include ptosis, diplopia Proximal muscle weakness

Question 31

Myasthenia gravis: treatment and diagnostics

Answer 31

AChE inhibitors - neostigmine: increases ACh activity at NMJ - endrophonium: short lived AChE inhibitor for diagnosis Other category of treatment is directed at immune system

Question 32

Spinal muscular atrophy

Answer 32

Floppy baby syndrome - one of the most common genetic causes of infant death - severity ant time of onset can vary greatly Death of lower motor neurone in anterior horn of spine - muscle atrophy -> hypotonia and muscle weakness - fibre type grouping - sensory system is spared

Question 33

Fibre type grouping

Answer 33

During spinal muscular atrophy Cycles of denervation are followed by collateral reinnervation Surviving axons innervate surrounding fibres Resulting in fibre type grouping In healthy muscles, motor units are intermingled During reinnervation, nearby surviving neurons re-innervate the denervated fibres, resulting in clusters

Question 34

Malignant hyperthermia

Answer 34

Genetic (rare) susceptibility to gas anaesthetics - e.g. sevoflurane Mutation in RyR means gas anaesthetic -> Ca2+ release - autosomal dominant - channel is suceptible if any of subunits are Results: SERCA works too hard Increase O2 consumption, increase CO2, acidosis, tachypnoea, muscles overheat, the body overheats, muscles are damaged, hyperkalaemia, muscle become rigid

Question 35

Muscular dystrophies

Answer 35

Group of inherited disorders Severe and progressive wasting of muscle - muscle weakness - due to myopathy, not neuropathy Waddling gait Contracture Cardiorespiratory muscle involvement - leads to death

Question 36

Duchenne muscular dystrophy

Answer 36

X linked disease Affects 1:3500 live male births - 1/3 cases arise spontaneously Progressive loss of muscle tissue Replaced by fibrofatty connective tissue Mutation: gene for dystrophin protein

Question 37

Causes of spinal muscular atrophy

Answer 37

Caused by genetic defect - SMN1 gene (required for survival of anterior horn neurones) - autosomal recessive - other genes cause similar syndromes

Question 38

Dantrolene sodium

Answer 38

Can stop abnormal calcium release in malignant hyperthermia Inhibits ryanodine receptor