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Physiology Review Sheet Striated Muscle Structure/Function, Muscle Performance, Muscle Protein Structure and Energetics, Smooth Muscle, Clinical Examples of Deranged Intramuscular Ca2+ Homeostasis Skeletal Muscle Structure [Note: not sure which parts you need to know for Micro and which for Phys] o myofibril (grouped into muscle fiber (multinucleated individual cell) which are grouped into muscle fascicles) sarcomeres (space between 2 Z bands) Z-band o thin filaments insert into this I band o light band (1/2 on each side of Z) o actin o length varies due to filaments sliding A band o dark band o myosin, actin o fixed length = length of thick filament H zone o light zone in center of A band o myosin M line o dark line in center of H zone o myomesin (M protein) o connects thick filaments o myofilaments thin filament – actin G-actin (globular) F-actin (filamentous) o 2 strands of F-actin forming a double helix (string of pearls) in muscle Tropomyosin o lies along actin groove o covers myosin binding sites during low Ca2+ levels Troponin o TnT – binds tropomyosin o TnC – binds Ca2+ and relieves inhibition of Tm o TnI – inhibits actin-myosin interaction at low Ca2+ thick filament – myosin single heavy chain and 2 light chains heavy chains o tail o role in filament assembly globular heads o S1 = head region ATPase activity actin binding site o S2 = hinge opposite polarity at center leaves central bare zone – no heads o reason for plateau in force-length curve Motor unit = a motor neuron and all the muscle fibers (cells) it innervates Mechanics o isometric: no change in total muscle length o o isotonic: constant load on muscle stimulation frequency sg stim = twitch = one nerve fires once and that motor unit contracts once second AP before relaxation is complete begins wave summation – new contraction occurs at greater force than previous one (temporal summation) treppe – high frequency of stimulation generates multiple contractions before any relaxation is complete resulting in a staircase appearance in force/time curve tetanus – treppe summates to smooth even contraction; note: if too high a frequency or for too long, force will decline Excitation-Contraction Coupling o more skeletal muscle structure sarcolemma aka plasma membrane of muscle cell electrically excitable; propagates APs like a nerve T tubules invaginations of sarcolemma (still excitable) open to ECF at A-I junction for fast skeletal muscle (at Z bands for others) sarcoplasmic reticulum stores and releases Ca2+ lots of Ca2+ pumps (Ca-ATPase) to sequester it in SR in longitudinal regions o phospholamban SR protein assoc with Ca-ATPase in slow skeletal, cardiac, and smooth muscle inhibits Ca-ATPase inhibited by phosphorylation (so pump can work) useful to increase cardiac contractility with certain drugs terminal cisternae o widened regions near junction with T tubules o Ca2+ stored here bound to calsequestrin o immediately next to T tubule = junctional SR triad T tubule flanked by SR on both sides ryanodine receptor (RyR) o foot proteins in terminal cisternae separating T tubule and SR membranes o Ca2+ release channel dihydropyridine receptor (DHPR) o voltage-gated Ca2+ channel (VGCC) o tons in T tubule adjacent to terminal cisternae o Contraction sequence of events (overview) motor neuron fires and elicits AP on sarcolemma AP propagates along sarcolemma and into T tubules signal causes conformational change in DHPR of T tubule to open the RyR of the SR releases Ca2+ Ca2+ binds troponin C actin and myosin interact, slide past each other, generate force Ca-ATPase in SR takes up excess Ca2+ inside cell and ends contraction Note: in cardiac muscle, EC [Ca2+] matters – DHPR is a Ca2+ channel in cardiac muscle and Ca2+ influx induces release of Ca2+ from SR via RyR Length-Tension Relationship Total force Active force o o o o force of contraction depends on length of sarcomere prior to contraction optimum length = max force total force – passive force = active force active force stimulated by contraction Note: active force declines at long and short lengths, but passive force continues to increase with length until muscle tears Force-Velocity Relationship o o o o o o o preload: initial length of muscle; stretch; determines max force possible afterload: additional load without changing muscle length; determines velocity hyperbolic relationship – velocity decreases rapidly with increased afterload power = F * V max power occurs at 1/3 max isometric force in skeletal muscle shorter muscles contract slower not very important in muscle because limited ROM due to skeleton very important in heart where muscle has a large length range Assembly of sarcomeres o in parallel = ↑ force o series = ↑ velocity, shortening capacity, and tension cost (ATPase) Factors influencing total force developed o [Ca2+]I -- # of activated actin filaments o # of crossbridges overlapped o # of crossbridges able to interact limited by speed o spatial summation due to motor unit firing (not all cells of unit are in same place; they are of same time) depends on: twitch duration of fibers (depends on myosin ATPase) frequency of firing # of motor units recruited size of motor units (# of fibers and fiber cross-section) o recruitment increase # of motor units firing small to large @ highest forces . . . increase force by increasing firing rate Sliding Filament Model of Contraction o tension of muscle fiber is proportional to extent of thick and thin filament overlap o insert graph B p10 at long lengths, less overlap between thick and thin filaments – can’t generate as much force at length = thick filament + 2 thin filaments (3.6 μm) – no overlap – no force at short lengths (?) – double filament overlap causes less ability to generate force ATP hydrolysis by mysoin releases heat – also dependent on degree of overlap between thick and thin filament o Thin filament regulation inhibition of actin-myosin interaction regulated by tropomyosin and troponin regulated by Ca2+ binding of TnC → conformational change to TnT and TnI → moves Tm off actin binding site on myosin [smooth muscle is regulated by thick filament] o Ca2+ sensitivity: sensitizers change Ca2+ binding affinity of TnC so that lower Ca2+ would affect more TnC and activate more actin phosphorylation of regulatory proteins alter Ca2+ signal transduction different isoforms of Tn and Tm modulate sensitivity o Crossbridge Cycle (occurs many times during contraction) myosin bound to ATP won’t bind actin myosin hydrolyzes ATP to ADP and Pi and binds actin (use 1 ATP / cycle) releases ADP and Pi (enhanced by actin binding) and undergoes power stroke (still linked to actin = rigor link) binds fresh ATP and dissociates from actin Muscle Metabolism o Fenn effect: isotonic contraction releases more energy than isometric contraction – feedback between mechanical constraints and rate of crossbridge cycling o Sources of ATP for contraction muscle stores of ATP low amounts immediately available creatine phosphate 3-5x as much as ATP very rapid Lohman Reaction o ATP ADP + Pi . . . . . . + . . . . . . PCr + ADP Cr + ATP (one step production of ATP) glycogen large stores can be metabolized by glycolysis (rapid, limited, lots of ATP, but relatively inefficient; make lactic acid) or by oxidative phosphorylation (slower, limited, huge amounts of ATP, efficient) exogenous stores (depends on diet) uses oxidative phosphorylation to generate lots and lots of ATP efficiently, but slowly Feedback mechanisms involve ADP & Pi Ca2+ o activate phosphorylase cascade to produce glucose from glycogen o increase permeability of sarcolemma to glucose increased blood flow o improve O2 flow o remove lactic acid o Recovery of oxygen consumption (oxygen debt) spring or burst of activity must resynthesize high energy phosphates used from PCr ultimately, nearly all ATP used in contraction is resynthesized during ox-phos Diversity of Proteins o Skeletal muscle contractile and regulatory proteins are NOT all the same – isoforms (myosin, actin, Tm, Tn) o Myosin isoforms (be familiar with varying characteristics) fast glycolytic (FG) white o type IIb high levels of fast ATPase few mitochondria dense SR large fiber diameter low oxidative enzyme activity low mitochondrial ATPase high glycolytic activity low myoglobin slow oxidative (SO) red type I low levels of slow ATPase intermediate # mitochondria intermediate SR intermediate fiber diameter high/intermediate oxidative enzyme activity intermediate mitochondrial ATPase low/intermediate glycolytic activity high myoglobin fast oxidative glycolytic (FOG) red type IIa high levels of fast ATPase lots of mitochondria dense SR small fiber diameter intermediate/high oxidative enzyme activity high mitochondrial ATPase intermediate/low glycolytic activity high myoglobin Cardiac Muscle o structure striated, sarcomeres similar to SO skeletal muscle sarcolemma with T tubules DHP receptor is a voltage sensor AND a Ca2+ channel – Ca2+ induced Ca2+ release (CICR) – not voltage gated as in skeletal Na+- Ca2+ exchanger o forward: Ca2+i exits, Na+e enters o reverse: Ca2+e enters (mechanism of ouabain and digitalis → inhibits Na+ pump →increases [Na+]i reverses pump and increases Ca2+i lots of mitochondria and lower PCr o function myocytes electrically coupled no recruitment. . . vary [Ca2+]i to regulate force mechanism for force generation the same for skeletal muscle less myofilaments in parallel – less force/unit cross sectional area energy cost is less → slower cross bridge cycling rate Smooth muscle o structure spindle-shaped cells proteins actin/myosin in scattered arrangement (no sarcomeres) o o fewer myosin filaments per actin dense bodies containing -actinin anchor actin intermediate filaments connect dense bodies to cytoskeleton poorly developed SR – can store Ca2+ no troponin energetics sustains contraction longer without fatigue & lower O2 consumption latch state: maintain force with reduced crossbridge cycling velocity force-length similar to skeletal oxidative contraction low energy requirements (supply=demand) low PCr pool (not needed) no oxygen debt glycolysis for membrane function lactate is produced under fully oxygenated conditions fuels membrane pumps (ATPases) metabolic compartmentation (have anaerobic and aerobic going on at same time) Smooth Muscle Excitation-Contraction Coupling General many types of Ca2+ channels and membrane receptors no fast Na+ channels AP carried via Ca2+ channels, and Ca2+ acts as second messenger automaticity o pacemaker potentials o slow waves (APs occur in bursts) oscillations in Nai-Ko pump act as stretch receptors (in GI tract, bladder, uterus, some blood vessels) neurotransmitters can activate mechanism of [Ca2+] I elevation → contraction Ca2+ entry via voltage-dependant channels and receptor operated channels Ca2+ release from SR via Ca2+ or IP3 o consequence of Ca2+ channels opening in PM o G-protein cascade with DAG or IP3 directly open Ca2+ in SR angiotensin II acts via G-protein activated phospholipase DAG and phosphorylation of PK-C activates slow Ca2+ channels – triggers release from SR IP3 acts as 2nd messenger activating SR Ca2+ channels reversed Na+/ Ca2+ exchange (follows gradient) inhibition of SERCA (SR Ca2+ reuptake pumps) mechanism of smooth muscle relaxation (lowering [Ca2+]i) – favored by high [Ca2+]i SERCA Na+/ Ca2+ exchanger in forward direction sarcolemma Ca2+ ATPase channels inhibition of sarcolemma Ca2+ channels transduction of Ca2+ signal at level of contractile filaments activation o Ca2+ binds calmodulin (free in cytosol) o Ca2+/calmodulin activates MLCK phosphorylates MLC 20 activates ATPase and allows crossbridge formation sliding filament relaxation o MLCP (phosphatase) (may regulate latch state) o dephosphporylates MLC 20 modulation of Ca2+ sensitivity Ca2+ entry blockers inhibit binding of Ca2+ /calmodulin to MLCK → less MLC phosphorylation stimulation of MLCP Malignant Hyperthermia o clinical features potentially fatal triggered by anesthetics (ether, or any of the –thanes) or muscle relaxants (succinyl choline) hyperthermia and muscle rigidity family history priming factors: stress, youth, prolonged surgery o Muscle Disorder a mild reaction increases creatine kinase survivors of severe reactions have rhambdomyolysis (severe destruction of muscle) abnormal sensitivity to halothane or caffeine o Porcine Stress Syndrome stress induced MH in pigs provides excellent clinical model (pathophysiology, treatment, molecular bio) o Molecular biology defect in RyR (triggers open and keep open) increase in Ca2+ ATPase activity (trying to pump Ca2+ back into SR) increase in myosin ATPase activity muscle metabolism increases to try to meet ATP demands depletion of ATP leads to cell death o Reaction early increase venous CO2, lactate, and temperature (anaerobic metabolism increasing) decreased venous O2 (increasing aerobic metab) increasing body temp indicates hypermetabolic state, but only Ca2+ reuptake channels working overtime because no muscle rigidity yet mid increasing body temp (even to baseline) muscle rigidity increased serum K+, Ca2+, catecholamines stressed systemic response late temp up to 43 C (109.4 F) lethal [K+], [Ca2+] muscle membrane failure CO2 tension above 100 mm o Dantrolene Sodium binds RyR (pH 6.5-7.5) inhibits Ca2+ release from SR, but does not shut off completely highly selective for muscle administered intravenously highly lipophilic (goes everywhere) reverses ongoing reaction and blocks future one wears off after ~ 12h Myophosphorylase Deficiency (McCardle’s Disease) o Clinical Features hereditary cramping, weakness, contractures (without AP) during high intensity activity o Impaired Muscle Glucose Metabolism glycogen metabolism problem =myophosphorylase deficiency – cannot go from glycogen to lactate o o o glucose metabolism = PFK deficiency – very similar both: muscle pain/ contractures muscle destruction can result Pathophysiology high intensity activity brings it on (anaerobic) aerobic activity is not a problem Problems of muscle ATP deficiency increased [Ca2+] – cannot pump back into SR myosin ATPase is uncontrolled (leave in rigor state) membrane integrity is lost leads to all other problems Ischemic Exercise Test test of serum lactate pre and post exercise test for these diseases