Molecular Basis of Muscle Contraction PDF

Molecular Basis of muscle contraction Dr. Rasha Abuelgasim Babiker MBBS, MSc, PhD Physiology Office 216 Department of Physiology [email protected] LEARNING OUTCOMES: 1. Explain the sequence of events from gen...

Molecular Basis of muscle contraction Dr. Rasha Abuelgasim Babiker MBBS, MSc, PhD Physiology Office 216 Department of Physiology [email protected] LEARNING OUTCOMES: 1. Explain the sequence of events from generation of action potential in the end plate to contraction & relaxation of the muscle. 2. Explain the Cross Bridge Mechanism Skeletal muscle contraction is preceded by the excitation of the muscle by the nerve fibre. EXCITATION – CONTRACTION COUPLING -events that occurs from excitation of muscle to its contraction  EXCITATION CONTRACTION COUPLING Steps of E-C coupling: Electromechanical coupling in skeletal muscles 1. Formation of an excitatory postsynaptic potential (EPSP) by sodium influx via the nicotinic acetylcholine receptor 2. Depolarization of the muscle cell membrane and opening of further voltage-dependent sodium channels 3. Formation of an action potential that spreads over the sarcolemma to the T-tubules 4. Conformational change of the membranous dihydropyridine receptor (DHPR) 5. Direct protein-protein interaction leads to opening of the coupled ryanodine receptor (RyR1). Subsequently, an influx of calcium from the sarcoplasmic reticulum into the sarcoplasm takes place. The resulting increase in calcium concentration is essential for the crossbridge cycle.  Molecular Mechanism of Contraction Sliding Filament Mechanism: Actin and Myosin slide upon each other and distance between two Z lines decreases, this called sliding filament theory, I band becomes smaller and may disappear, A band does not change. Crossbridge cycle/ walk-along theory:  The crossbridge cycle: The crossbridge cycle 1. Released state: the myosin binding site on the actin filament is blocked by tropomyosin → no interaction between myosin and actin. The myosin head is in a low-energy 45° position with ATP bound to it. 2. Cocked state: ATP is hydrolyzed, yielding ADP and phosphate → cocking of myosin head (high-energy 90° position). The myosin binding site remains blocked. 3. Crossbridge state: activation of muscle cell with influx of calcium. Binding of calcium to troponin → tropomyosin is displaced from myosin binding site on actin filament → myosin head binds to actin filament (crossbridge formation). 4. Power stroke: release of the phosphate bound to the myosin head → power stroke of myosin head → myosin head moves along the actin filament. This action results in muscle contraction and/or tension, depending on the situation. Afterward, the myosin head returns to the low-energy 45° position. 5. Detached state: release of ADP → binding and hydrolyzation of a new ATP molecule and subsequent release of the myosin head. If the calcium concentration remains high, the crossbridge cycle starts again. If the calcium concentration decreases, the myosin binding site is once again blocked by tropomyosin and the crossbridge cycle ends.  Relaxation occurs when Ca2+ is reaccumulated by the SR Ca2+- ATPase (SERCA). Intracellular Ca2+ concentration decreases, Ca2+ is released from troponin C, and tropomyosin again blocks the myosin-binding site on actin. As long as intracellular Ca2+ concentration is low, cross-bridge cycling cannot occur. Troponin I furthers inhibits interaction between Actin and Myosin and muscle relaxes. Mechanism of tetanus. A single action potential causes the release of a standard amount of Ca2+ from the SR and produces a single twitch. However, if the muscle is stimulated repeatedly, more Ca2+ is released from the SR and there is a cumulative increase in intracellular [Ca2+], extending the time for cross-bridge cycling. The muscle does not relax (tetanus). MALIGNANT HYPERTHERMIA It is triggered in susceptible individuals primarily by the volatile inhalational anesthetic agents and the muscle relaxant succinylcholine Mutation of Ryanodine receptor: Leads to persistent high levels of ICF Calcium. Hence the muscles remain in a state of hyper contracture leading to increased muscle metabolism and heat production. Questions? Q1 What is Rigor Mortis? Q2 ATP is needed for 3 things; what are they? Is muscle relaxation a passive or active process?  https://next.amboss.com/us/article/so0tWS?m=-7bDoE