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Flashcards in Physiology of skeletal muscle Deck (12):

Thick filaments

-Myosin fibers consisting of the myosin head (2) and myosin heavy chains (2, one for each head)
-Crossbridges btwn thin filaments and thick filaments occur at the myosin heads (N-terminus)


Thin filaments

-Composed of actin, tropomyosin and troponin (many kinds of troponin, but for skeletal muscle most important is TnC)
-Tropomyosin/TnC complex covers the actin fiber and prevents myosin from binding to its binding site on actin
-Binding of Ca to TnC leads to change in conformation of TnC and tropomyosin, leading to them sliding off the myosin binding site on actin
-Myosin binds to actin and initiates muscle contraction


Generation of mechanical work 1

-When myosin binds to actin it does so at 90 degrees, then swivels to 45 degrees causing the tin filaments to be pulled towards each other
-This is a cycle requiring ATP, with the cycle starting w/ rested muscle
-At rest there are no cross bridges, but ATP has already been hydrolyzed to ADP + Pi b/c the myosin ATPase has a constitutively low activity even w/o the presence of Ca (w/ Ca there is binding of actin and myosin which greatly increases the ATPase activity)
-When Ca enters the myofiber cross-bridges are formed btwn the actin and myosin


Generation of mechanical work 2

-Once cross-bridge is formed the ADP+Pi are released from myosin (rate limiting step and movement phase of the cycle)
-Release of ADP/Pi results in contraction of the sarcomeres and thus the muscle (the myosin heads bend to 45 deg)
-To relax the muscle there must be ATP to bind to myosin, which causes a conformational change and leads to low affinity for actin
-This breaks the cross-bridges, but soon after this the ATP is hydrolyzed to ADP/Pi (is immediate if muscle is still contracted)
-This results in there being no cross-bridges and ADP/Pi bound to myosin, thus beginning the cycle again


Excitation-contraction coupling

-Ach released on the motor end plate results in rapid depolarization of the muscle membrane (end plate potential)
-If APs are induced in a large enough frequency (before the muscle can relax), the APs will cause the muscle to increase its force of contraction
-The AP is conducted along sarcolemma, down T-tubules and results in the release of Ca from the SR
-Relaxation is achieved by returning Ca from cytoplasm to SR by Ca-transport ATPase which pumps Ca into SR
-Thus ATP is required for relaxation and contraction
-Some of the energy from ATP hydrolysis is released as heat


Malignant hyperthermia

-Mutations in the ryanodine receptor (SR Ca release channel) cause Ca to leak out of SR leading to sustained muscle contraction
-This induces large amounts of ATP consumption and generation of heat
-Usually asymptomatic, but when they undergo surgery and receive volatile anesthetics, those trigger a sudden and prolonged release of CA from the SR
-This can be fatal if not Rx w/ IV dantrolene, which prevents the release of Ca from the SR



-The absence or mutations of dystrophin (cytoskeletal protein) causes various forms of muscular dystrophies
-Duchenne's muscular dystrophy: dystrophin is either absent or present in very low levels
-Becker's muscular dystrophy: dystrophin is present but mutated and non-functional


Inducing larger contractions

-2 ways to get larger contractions
-Recruit bigger motor units: smaller aMNs (conduct APs slower, innervate fewer fibers, but are stimulated very easily by PMC) are activated first
-Larger aMNs (conduct APs faster, innervate more muscle fibers, but take larger stimuli from PMC to activate) are activate last only when they are needed
-One other way: increase the frequency of aMN firing to induce tetanus (max force generation)


Hyperkalemic periodic paralysis

-Mutations of V-gated Na channels prevent normal inactivation after opening of the Na channel
-Sustained depolarization results in block of further APs and muscle weakness (can be see myotonia)
-High blood K makes it worse b/c it makes the muscles harder to hyper polarize (less K leaves muscle)


Hypokalemic periodic paralysis

-Can be from mutations in V-gated NA channels cause them to inactive too quickly, too easily, and for longer periods of time (closed state is favored)
-This causes the muscle cell to be perpetually hyperpolarized and thus paralysis
-Most patients have mutations in Ca channel (S4 segment, V-sensitive region) which decreases Ca current and thus prevents muscle contraction
-Relationship w/ K blood levels not understood, but low K makes it worse
-Will never see myotonia (inability to relax muscle)


Paramyotonia congenita

-S4 segment of Na channel mutated, resulting in slow inactivation of Na channels
-This leads to favor of the open state and constant depolarizations of muscles
-Exacerbated by cold and exercise


Myotonia congenita

-Mutation in Cl channel of T tubules (Cl enters the cell thru T tubules as K leaves the cell to hyperpolarize the muscle)
-In MC, Cl cannot enter the muscle during hyper polarization when K leaves
-This leads to the cells being permanently depolarized (and muscle contracted) for a period of time