Skeletal Muscle

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Skeletal Muscle

Skeletal Muscle


OutlineStructureMolecular mechanism of contractionMolecular characteristics of contractileproteinsInteraction between myosin and actin onmuscle contractionNeuromuscular junction


Skeletal muscleSkeletal muscle, 40 % of body massSmooth muscle, cardiac muscle, 5-10 % of bodymassSkeletal muscle- voluntary, striated, multinucleate,terminal cellSmooth muscle-involuntary, non-striated,uninucleate, can undergo mitosisCardiac muscle, involuntary, striated, uni- orbinucleate nuclei, slow dividing, terminal cell


NomenclatureSarcolemma- plasma membraneSarcoplasmic reticulum- endoplasmicreticulumMuscle fiber- cellMyofibril-subcellular fibersSarcomere - functional unit of myofibril


Muscle zonesA band = thick and thin filamentsI band = thin filaments onlyZ line = actin attachment pointH band = thick filaments only


Molecular Mechanism ofContractionSliding filament theory of contractionShortening of the sarcomereincreased overlap between thick and thinfilaments


Optimal overlap between thick and thin filaments


Molecular CharacteristicsMyosin (thick filament)actin binding domainATPase siteATP bindingmolecular hinges


Myosin:•Actin binding site•ATP/ADP bindingsites•ATPase site


Actin Thin Filament


Troponin


Troponin•T, tropomyosin binding site•C, calcium binding site•I, inhibitory site


Cross-bridges on either side of the thick filament face each other.


Excitation-contractioncouplingMuscle cells are irritable,ie., depolarizewhen electrically stimulatedNicotinic (Ach) receptors on thesarcolemma are ligand-regulated Na +channelsWhen Ach binds, Na + enters and muscledepolarizesThe motor nerves innervating skeletalmuscle originate in the ventral horn of thespinal cord (somatic motor NS) and arecholinergic


Excitation-contractioncouplingMotor unit=motor nerve and fibers


End plate potential


AP causes Ca 2+channels in SER to open


Neuromuscular junction


Recruitment of Motor UnitsMuscle fiber contracts in an “all-ornothing”fashionHow do whole muscles contract in agraded or proportional fashion?Answer: Differential recruitment of motorunits.


Neuromuscular junctionSpecialized synapses between cholinergic motorneurons and skeletal muscleEach motor neuron may innervate 1-100individual muscle fibersEach muscle fiber innervated by only one motorneuron1 motor neuron and all muscle fibers itinnervates is called a motor unitAcetylcholinesterase- enzyme in the cleft thatdegrades acetylcholine


Synapse is 1/5000the thickness ofpaper


DHPR,dihydropyridinereceptor- voltagesensitiveRyR, ryanodinecalcium channelcalciumexitsthrough this fromthe SR intocytoplasm


Ryanodine ReceptorCalcium ions diffuse down theirconcentration gradient through ryanodinereceptors (RyR) in the sarcoplasmic/endoplasmic reticulumRyRs are transmembrane proteins of 565kDa that form tetrameric (four domains)Ca 2+ channels


DHPR, dihydropyridinereceptor form of voltage-dependent Ca 2+channelvoltage conductor that conveysdepolarization of T-tubulemembrane to Ca 2+ release throughthe ryanodine receptor in the SR


Model of SR Ca2+ release channel activity underlying sparks terminated by voltagedependentand voltage-independent mechanisms.Calcium sparkLacampagne A et al. PNAS 2000;97:7823-7828©2000 by The National Academy of Sciences


Clinical Correlations Drugs that interfere with neuromuscular junctionnicotine- binds irreversibly to nicotinic receptorsAcetylcholinesterase inhibitors- neostigmine,prolonged muscle contractionCurare- poison dart frog skin, blocks Achreceptors, muscle relaxationStrychnine-inhibits glycine input to motor neurons in spinal cord.Strychnine causes disinhibition of motor neurons, overactivationof motor neurons and convulsions


Clinical Correlations(con’t)Amyotrophic lateral sclerosis (ALS)- Lou Gehrig’sdisease.Scar tissue forms around motor neurons.Death of motor neurons and muscle weakness.90% of cases have no causeMyasthenia gravis- autoimmune disease thatattacks muscle nicotinic receptors


Toxins from Clostridiumbacteria that affectpresynaptic motorterminals:•Tetanus toxin•Botulinum toxincleave the vesicleSNARE protein,synaptobrevin© 2001 by Sinauer Associates, Inc.


Cardiac muscle


STOP!


Actin (thin) filamentPolymerized chain of G actin - calledfilamentous actin (F actin). Double helixtropomyosin- wraps around actin,covers myosin binding domaintroponin- 3 subunits attached at periodiclocations along tropomyosin fibertropomysin binding domaincalcium binding domain


Interaction Between Actin andMyosin to Cause Contraction Pure actin and myosin will bind to each other readily If troponin-tropomyosin complex added, inhibits actinand myosin binding, therefore active binding sites onactin filament are blocked by troponin-tropomyosincomplex When calcium ions bind to troponin, active binding sitesare uncovered and conformational change allows myosinto bind to actin As sites become uncovered, myosin binds to actin


isometricisotonic


T-tubules Application of small amounts of electrical current aroundZ line, but not other areas, is capable of producing acontraction Anatomical studies in frog muscle indicated a series ofsarcolemma invaginations that carry current to innermyofibrils- T-tubules Each T-tubule bordered on either side by swollen regionof sarcoplasmic reticulum, lateral or terminal cisterna(e);together this structure is called a triad Cardiac muscle similar, 1 T-tubule and 1 lateral cisterna= Diad


ATP conservationIf muscle is stimulated, ATP levels don’tchangeCreatine phosphate is a muscle storageform of phosphate

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