Regulation of Skeletal Muscle Contraction

Contraction Under Control of Voluntary Nervous Stimulation

Motor neuron can branch and innervate multi cells

Neurons make hundreds of synapses on a single fiber

Sequence: A/P reaches neuron terminus, then acetylcholine vesicle is released into synaptic cleft

Nicotinic muscle AchR is found at many nerve muscle junctions

A/P spreads across Sarcolemma to T- Tubules; signal is transferred to the sarcoplasmic reticulum via the Terminal Cisterna

dihydropyridine receptor (DHPreceptor) aka T-tubule voltage sensing Ca²⁺channel protein which contacts

ryanodine receptor aka SR Ca²⁺ channel protein: senses DHPR conformational change which opens to release Ca²⁺ from SR to cytoplasm

SR contains large stores of Ca²⁺

during stimulation, cytosolic [Ca²⁺] increases from .1uM to 10 uM due to above response
during cessation of stimulation, [Ca²⁺] decreases due to a Ca²⁺/ATPase pump in SR membrane

Mechanism of Contraction

Steric hindrance of the contractile cycle by tropomyosin/troponin

tropomyosin filaments periodically studded with troponin run along (not in) actin 2X helix, blocking myosin binding site on F-actin
during Ca²⁺ flood upon stimulation, Ca²⁺ binds to troponin-C leading to induced shift of tropomyosin complex toward groove of actin filament
exposed actin binding site allowing actomyosin contractile cycle to begin causing muscle contraction

Troponin Subunit

Tn-C: binds Ca – related to EF Hand family of Ca binding pps (includes calmodulin)

Tn-I: Inhibitory subunit. Blocks actomyosin ATPase cycle when assembled with thin filaments and tropomyosin

Transients during excitation contraction coupling

within a few msec of A/P on membrane Ca is released by SR; cytosolic [Ca²⁺] peaks at 10 msec
from 10-40msec Ca binding of troponin peaks
force output of single twitch peaks after most Ca has been re-sequestered and as Ca binding of troponin diminishes

Mechanisms by which force output is graded

tetnus = many action potentials sufficient to maintain elevated cytosolic [Ca²⁺] resulting in continuous actomyosin crossbridging
variable recruiting of motor units also produces graded force

the amount of force a sarcomere generates depends on the # of heads in binding position

Malignant hyperthermia

defect in ryanodine receptor results in sustained muscle contraction leads to elevated metabolic activity and greatly increased heat production

in humans is induced by halothane

in pigs is result of stress in genetically predisposed individuals