Physiology of skeletal muscle

Question 1

Thick filaments

Answer 1

• 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)

Question 2

Thin filaments

Answer 2

• 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

Question 3

Generation of mechanical work 1

Answer 3

• 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

Question 4

Generation of mechanical work 2

Answer 4

• 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

Question 5

Excitation-contraction coupling

Answer 5

• 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

Question 6

Malignant hyperthermia

Answer 6

• 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

Question 7

Dystrophies

Answer 7

• 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

Question 8

Inducing larger contractions

Answer 8

• 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)

Question 9

Hyperkalemic periodic paralysis

Answer 9

• 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)

Question 10

Hypokalemic periodic paralysis

Answer 10

• 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)

Question 11

Paramyotonia congenita

Answer 11

• 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

Question 12

Myotonia congenita

Answer 12

• 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