6. Pathophysiology of skeletal muscle Flashcards
Plasticity of skeletal muscle: exercise
muscle is extremely plastic
adapts to changes in functional demand:
Endurance exercise
Responds to total contractile activity
Resistance training
Responds to loading & stretch
muscle plasticity: adaptations
adaptations:
- structural e. g. size, capillarisation - contractile properties e. g. fibre type transitions
adaptability occurs from embryogenesis
into maturity
Structural adaptation
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 & vascularisation
some muscles enlarge by between 15-50%
effect of endurance exercise
E.g. distance running, cycling or swimming
(low force, high contractile frequencies)
increased:
- fibre diameter (slight) - blood supply (Increased oxidative capacity) - mitochondrial content
will express increase in oxidative enzymes
fibres become slower
gradual transformation of type IIX to type IIA (or to type I?)
Non-endurance exercise
conversion to type IIX
from type IIA
greater muscle force & strength
increase in type IIX fibre size due to increase in numbers of sarcomeres & myofilaments -> increase in power
results in much larger muscles (bulk)
Ice
To reduce swelling By reducing perfusion After an acute injury Sprain After exercise in overuse injury
Heat
To relax and loosen tissues
Use before activities that irritate chronic injuries
Strain
Increases blood flow
Aspirin and MSK pain
Aspirin is an NSAID
Reduces pain
Reduces inflammation
Used for musc-skel pain Chronic diseases Osteoarthritis Sports injuries Combined with ice Often after exercise
Mechanism of aspirin
Mechanism
Inhibits COX
Reduces synthesis of prostaglandins
Part of arachidonic acid pathway
Arachidonic acid and prostaglandins have many effects
Gastro-intestinal adverse effects of chronic aspirin
Stomach bleeding
Ulcers
Anabolic effects of testosterone
Anabolic effects of testosterone:
Increases protein synthesis
Decreases catabolism (by opposing cortisol & glucocorticoids)
Reduces fat: increase BMR, increase differentiation to muscle (rather than fat cells)
Effects of anabolic steroid abuse
anabolic steroid abuse - 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
Effect of spaceflight
Decreased weight-bearing
Humans – transition of type I fibres to type IIA/X fibres
Decreased relative muscle mass - all muscles undergo some atrophy, but predominantly weight-bearing muscles
Effect of bed-rest
transition of type I fibres to type IIA
weight-bearing muscle atrophy:
- Decreased muscle protein synthesis
- myofibrillar breakdown
- Decreased strength (due to decreased size)
- Loss of type I fibres
Treat by resuming minor activity early. Add physiotherapy to prevent contractures.
Contracture
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
Skeletal muscle cells structure
Skeletal muscle cells are multinucleate
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 usually impossible
What enlardes skeletal muscle
Skeletal muscles are enlarged by:
Fibre enlargement
Increased vascularisation
Muscle regeneration
During inflammation and degeneration of damaged muscle tissue
previous quiescent myogenic cells, called satellite cells, are activated
These proliferate, differentiate and fuse onto extant fibres
They contribute to forming multinucleate myofibers
Myosatellite cells
Progenitor cells in muscle Also called “satellite cells” NOT related glial satellite cells Essential for regeneration & growth Most are quiescent Activated by mechanical strain Activation —> proliferation & differentiation
Myalgia
Muscle pain
Causes of myalgia:
Injury, overuse, infections, auto-immune
Can by associated with Rhabdomyolysis
Myopathy
Muscular weakness due to muscular muscle fibre dysfunction
Cf. neuropathy & 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
Myo + pathy = “muscle disease”
Dys + trophy = “incorrect nourishment/growth”
Paresis
weakness of voluntary movement, or
partial loss of voluntary movement or
impaired movement
Usually referring to a limb
From Greek “to let fall”
Involuntary twitches
Fasciculations and fibrillations
Fasciculations
fasciculations : involuntary visible twitches in single motor units (neurogenic), which 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
Fibrillations
fibrillations : involuntary spontaneous contractions of individual muscle fibres (myogenic) invisible to the eye but identified by electromyography
Rhabdomyolysis
Rapid breakdown of skeletal muscle
Risk of kidney failure
Treatment:
Intravenous fluids (to treat shock)
possibly haemodialysis, etc
Why is there risk of kidney failure in rhabdomyolysis
Cellular proteins (esp myoglobin) released into blood can “clog” renal glomeruli Urine is “tea coloured”, no urine produced 12 hours after injury Leads to electrolyte changes: hyperkalaemia
Causes of rhabdomyolysis
Causes of rhab (ie when cell membrane loses integrity) Trauma: Crush injury Drugs adverse effects of: statins or fibrates Hyperthermia Ischaemia to the skeletal muscle Compartment syndrome, thrombosis
rhabdomyolysis symptoms and signs
Symptoms & signs (depending on severity)
muscle pains
vomiting and confusion
Dark urine
Serum levels CPK: diagnostic
Creatine Phosphokinase
CK or CPK abbreviations used interchangeably
The enzyme, not creatine phosphate
distinct forms of CPK found in different tissues
skeletal muscle CPK isoform is CK-MM
cardiac muscle CPK isoform is CK-MB
when tissue damaged and cells lyse there is a release of tissue specific CK from cells into blood
Elevations in CK-MM occur after skeletal muscle trauma or necrosis
muscular dystrophies, polymyositis and rhabdomyolysis
Test = “Total CK” (CK-MM is not a clinical test)
Myoglobin: diagnostic
“Buffers O2” Protein + Haem group “tea coloured” In plasma indicates 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+
Nb: decrease in serum K = cause of rhabdo,
Increase in K= result of rhabdo
Rigor mortis
ATP depleted after death
Muscle cell does not resequester Ca2+ into SR
Increase in Cytosolic Ca2+
Ca2+ allows crossbridge cycle contraction
Until ATP & creatine-P run out
W/o ATP -> myosin stops just after power stroke
With myosin still bound to actin
Rigor mortis ends when muscle tissue degrades after 3 days
Myasthenia gravis
progressive muscle weakness and fatigability
Often starts with eye muscles
Caused by depletion of nAChR
arises as the immune system inappropriately produces auto-antibodies against nAChR
Pathophysiology of myasthenia gravis
less depolarisation of muscle fibres
many fibres do not reach threshold
repeated stimulation -> neuromuscular fatigue
symptoms include ptosis, diplopia,
with weakness in eyelid and extraocular muscles
proximal muscle weakness
MG: treatment and diagnosis
AChE inhibitors
Neostigmine
Increase ACh activity at NMJ. ACh released from nerve terminals into synapse not rapidly catabolised but can bind to the remaining AChRs for longer time
Edrophonium (a/k/a tensilon): short-lived AChE inhibitor for diagnosis, temporarily improves symptoms eg ptosis
Other category of treatment is directed at immune system
Thymectomy – reduces symptoms in 70% of patients. Exact mechanism unknown. Rebalance immune system?
use of immunosuppressive drugs e.g. corticosteroids
plasmapheresis = removal of anti AChR antibodies from blood stream
Spinal muscular atrophy
a/k/a Floppy Baby Syndrome
One of most common genetic causes of infant death
Severity and time of onset can vary greatly
death of lower motor neurons in anterior horn of spine
Muscle atrophy —> hypotonia & muscle weakness
Via apoptosis
Fibre type grouping
Sensory system is spared (b/c not in anterior horn)
Caused by genetic defect SMN1 gene Required for survival of anterior horn neurons Autosomal recessive Other genes cause similar syndromes
Fibre type grouping
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
Malignant hyperthermia
Genetic (rare) susceptibility to gas anaesthetics
Eg sevoflurane
Mutation in RyR means gas anaesthetic -> Ca2+ release
Autosomal Dominant
Channel is susceptible if any of subunits are
Result: SERCA works too hard (to pump Ca back into SR)
increased O2 consumption, increased CO2, acidosis, tachypnea, muscles overheat, the body overheats, muscles are damaged (rhabdomyolysis), hyperkalaemia, muscles become rigid
How does malignant hyperthermia occur?
Muscle cells open and leak their contents
Plasma CK-MM increases
Kidney failure possible: urine red from myoglobin
dantrolene sodium can stop the abnormal calcium release
Inhibits ryanodine receptor
Muscular dystrophies
group of inherited disorders severe and progressive wasting of muscle muscle weakness Due to myopathy, not neuropathy waddling gate contractures cardiorespiratory muscle involvement
Duchenne muscular dystrophy
x-linked disease affects 1:3500 live male births one third of cases arise spontaneously progressive loss of muscle tissue replaced by fibrofatty connective tissue Mutation: gene for dystrophin protein
