Pathophysiology of Skeletal Muscle 2023-04-14(2).ppt

Exercise Plasticity Signs Pathophysiology of Skeletal Muscle Failures in Coordination, Force and Plasticity Brighton and Sussex Medical School Diseases Rhabdomyol Dr. Harry Witchel 1 Exercise Plasticity Learning Objectives Effects of exercise  Endurance vs non-endurance exercise  Ice, Hea...

Exercise Plasticity Signs Pathophysiology of Skeletal Muscle Failures in Coordination, Force and Plasticity Brighton and Sussex Medical School Diseases Rhabdomyol Dr. Harry Witchel 1 Exercise Plasticity Learning Objectives Effects of exercise  Endurance vs non-endurance exercise  Ice, Heat and Aspirin Plasticity, Regeneration & Recovery Signs  Effects of bed rest & space flight  Satellite cells Signs, Symptoms & Myopathy Diseases Rhabdomyol  Myalgia, Paresis Rhabdomyolysis & Diagnostics  CPK, Myoglobin Diseases & Therapeutics  Myasthenia Gravis  Spinal Muscular Atrophy  Malignant Hyperthermia  Introduction to Muscular Dystrophy 2 Exercise Plasticity Signs Tortora (Global ed.)  Chapter 10 Guyton & Hall (14th ed.)  Review chapters 6, 7 & 85  (not particularly thorough on this topic) Diseases Rhabdomyol Recommended Reading 3 muscle is extremely plastic adapts to changes in functional demand: Exercise Diseases Rhabdomyol Signs Plasticity Plasticity of skeletal muscle: exercise Endurance exercise Responds to Total Contractile activity Resistance training Responds to Loading & stretch 4 Exercise Plasticity Signs Rhabdomyol Diseases muscle plasticity: adaptations adaptations: - structural e.g. size, capillarisation - contractile properties e.g. fibre type transitions Wheater's Functional Histology adaptability occurs from embryogenesis into maturity 5 Exercise Plasticity Signs Rhabdomyol Diseases 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% 6 e.g. distance running, cycling or swimming (low force, high contractile frequencies) increased: - fibre diameter (slight) - blood supply ( oxidative Exercise Diseases Rhabdomyol Signs Plasticity effect of endurance exercise capacity) - mitochondrial content will express  in oxidative enzymes fibres become slower gradual transformation of type IIX to type IIA (or to type I?)7 Exercise Plasticity Signs Rhabdomyol Diseases non-endurance exercise conversion to type IIX • from type IIA • greater muscle force & strength  in type IIX fibre size due to  in numbers of sarcomeres & myofilaments results in much larger muscles (bulk)  POWER 8 Exercise Plasticity 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 Diseases Rhabdomyol Signs Ice and Heat 9 Exercise Plasticity Signs Aspirin and Musculoskeletal Pain Aspirin    is an NSAID So is ibuprofen Reduces pain Reduces inflammation Used for musc-skel pain  Chronic diseases Diseases Rhabdomyol • Osteoarthritis  Sports injuries • Combined with ice • Often after exercise 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 10 Diseases Rhabdomyol Signs Plasticity Exercise Testosterone has anabolic & androgenic effects 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) 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 11  weight-bearing Diseases Rhabdomyol Signs Plasticity Exercise effect of spaceflight humans – transition of type I fibres to type IIA/X fibres  relative muscle mass - all muscles undergo some atrophy, but predominantly weightbearing muscles 12 Exercise Plasticity Signs Rhabdomyol effect of bed-rest transition of type I fibres to type IIA weight-bearing muscle atrophy -  muscle protein synthesis - myofibrillar breakdown -  strength (due to  size) - loss of type I fibres Diseases Clinica Sandalf treat by resuming minor activity early. Add physiotherapy to prevent contractures. 13 Diseases Rhabdomyol Signs Plasticity Exercise Summary Fibre Types 14 Exercise Plasticity Signs Rhabdomyol Diseases 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 – Vocabulary sheet lists movies demonstrating this 15 Exercise Skeletal muscle cells are multinucleate Plasticity They develop as myoblasts  Which are mononucleate  Then the myoblasts fuse The multinucleate cells do not divide  Mitosis with multiple nuclei usually impossible Diseases Rhabdomyol Signs The nuclei are peripheral Skeletal muscles are enlarged by:  Fibre enlargement  Increased vascularisation 16 During inflammation and degeneration of damaged muscle tissue Exercise Diseases Rhabdomyol Signs Plasticity Muscle Regeneration previously quiescent myogenic cells, called satellite cells, are activated  These proliferate, differentiate and fuse onto extant fibres  They contribute to forming multinucleate myofibers 17 Exercise Plasticity Signs 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 Diseases Rhabdomyol Myosatellite cells 18 Exercise Plasticity Signs Rhabdomyol Diseases Developmental Biology General principle in the body  Quiescent Cells Waiting for Damage  When damage occurs, they “activate”  Activated cells • Migrate • Produce new proteins • Differentiate to “fill in” or fix damage Examples:  Bone osteoblast precursors  Skeletal muscle satellite cells  Platelets & many more 19 Exercise Plasticity Muscle pain Causes of myalgia:  Injury, overuse, infections, auto-immune Can be associated with Rhabdomyolysis Diseases Rhabdomyol Signs Myalgia 20 Exercise Plasticity Signs Rhabdomyol Diseases Myopathy Muscular weakness due to muscle fibre dysfunction  Cf. neuropathy & neurogenic disorders • Failure to contract 2 possible causes: • 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” 21 Exercise Plasticity Signs weakness of voluntary movement, or partial loss of voluntary movement or impaired movement Usually referring to a limb From Greek “to let fall” Diseases Rhabdomyol Paresis 22 Exercise Plasticity Signs 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 : involuntary spontaneous contractions of individual muscle fibres (myogenic) invisible to the eye but identified by electromyography – Vocabulary sheet lists movies demonstrating these Diseases Rhabdomyol Involuntary Twitches 23 Exercise Plasticity Signs Rhabdomyol Diseases Rhabdomyolysis Rapid breakdown of skeletal muscle  Not cardiac muscle, not myocardial infarct Risk of kidney failure  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 Treatment:  Intravenous fluids (to treat shock)  possibly haemodialysis, etc Rhabdo + myo + lysis = striped (ie skeletal) muscle breakdown 24 Exercise Plasticity Rhabdomyolysis Causes of rhab (ie when cell membrane loses integrity)  Trauma: Crush injury  Drugs Signs • adverse effects of: statins or fibrates  Hyperthermia  Ischaemia to the skeletal muscle Diseases Rhabdomyol • Compartment syndrome, thrombosis Symptoms & signs (depending on severity)  muscle pains  vomiting and confusion  dark urine 25 Exercise Plasticity serum levels CPK: Diagnostic Creatine Phosphokinase  CK or CPK abbreviations used interchangeably  The enzyme, not creatine phosphate Diseases Rhabdomyol Signs 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 typical clinical test) 26 Exercise Plasticity Signs Rhabdomyol Diseases Myoglobin: Diagnostic Function: “Buffers O2” Structure: Protein + Haem group Appearance: “tea coloured” Clinical use: In plasma it 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+ Urine from patient with rhabdomyolysis  Nb:  serum K = cause of rhabdo,  K = result of rhabdo 27 Exercise Plasticity Signs ATP depleted after death Muscle cell does not resequester Ca2+ into SR  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 Diseases Rhabdomyol Rigor Mortis 28 Caused by depletion of nAChR arises as the immune system inappropriately produces auto-antibodies against nAChR  See online videos listed in vocab list 29 Core Memorisation Exercise Plasticity Signs progressive muscle weakness and fatigability  Often starts with eye muscles Diseases Rhabdomyol myasthenia gravis Exercise Plasticity myasthenia gravis less depolarisation of muscle fibres  many fibres do not reach threshold Signs Ptosis repeated stimulation  neuromuscular fatigue  with weakness in eyelid and extraocular muscles proximal muscle weakness Diseases Rhabdomyol symptoms include ptosis, diplopia, 30 Exercise MG: Treatment & Diagnostics Signs Plasticity AChE inhibitors Pyridostigmine 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 Rhabdomyol Other category of treatment is directed at immune system Thymectomy – reduces symptoms in 70% of patients. Exact mechanism unknown. Rebalance immune system? Diseases use of immunosuppressive drugs e.g. corticosteroids plasmapheresis = removal of anti AChR antibodies from blood stream 31 Exercise Plasticity Signs Rhabdomyol Diseases Spinal Muscular Atrophy (SMA) 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 it is not in anterior horn) Caused by genetic defect  SMN1 gene • Required for survival of anterior horn neurons  Autosomal recessive  Other genes cause similar syndromes 32 Exercise Plasticity Signs Rhabdomyol Diseases 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 (Figure A), motor units are intermingled. During reinnervation, nearby surviving neurons re-innervate the denervated fibres, resulting in clusters (Figure B) Muscle biopsy to assess fibre types Type II fibre atrophy due to lower motor neuron pathology 33 Core Memorisation Exercise Plasticity Signs 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)  O2 consumption,  CO2, acidosis, tachypnea, muscles overheat, the body overheats, muscles are damaged (rhabdomyolysis), hyperkalaemia, muscles become rigid Diseases Rhabdomyol Malignant Hyperthermia 34 Exercise Plasticity Kidney failure possible: urine red from myoglobin Plasma CK-MM increases dantrolene sodium can stop the abnormal calcium release  Inhibits ryanodine receptor Diseases Rhabdomyol Muscle cells open and leak their contents Signs malignant hyperthermia 35 Exercise Plasticity Signs Rhabdomyol Diseases 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 dys + trophy = “bad growth”, ie cell death Muscle fibres (purple) are replaced by fat (black) BBC News – Health July 25 2011 36 Core Memorisation Exercise Plasticity 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 Diseases Rhabdomyol Signs Duchenne muscular dystrophy Gower’s sign 37 Exercise Plasticity Signs Rhabdomyol Summary Lack of muscle use can lead to contractures or atrophy  Duchenne muscular dystrophy – dystrophin (X-linked) Exercise training —> hypertrophy <— satellite cells proliferate Rhabdomyolysis  Crush injury Diagnostic Tests  Oxygen carrier in urine: myoglobin  Energy for contraction: creatine phosphokinase  Biopsy to show regeneration: fibre type grouping EC coupling: rigor mortis & malignant hyperthermia Diseases Pharmacology: AChE Inhibitors (MG), Dantrolene (MH) Insufficient neural signalling: myasthenia gravis & SMA 38