This document was created by Alex Yartsev ([email protected]); if I have used your data or images and forgot to reference you, please email me. Skeletal Muscle Physiology First of all, which muscle is which - Skeletal muscle: o Well-developed cross-striations o Does not contract in absence of a nerve stimulus o The individual muscle fibers DO NOT connect functionally or anatomically (i.e. they don’t form a single sheet of cells, and one fiber’s action potential wont get transmitted to the next) o Generally, skeletal muscle is under voluntary control - Cardiac muscle: o Also has cross-striations o Is functionally syncytial: cells are connected well enough to conduct action potentials to one another o Can contract on its own, without stimulus (but this is under some control via the autonomic nervous system, which modulates its activity) - Smooth muscle: o Has no cross-striations o Two broad types: . VISCERAL or “unitary” smooth muscle: Functionally syncytial, action potentials propagate from cell to cell Contains pacemakers which discharge irregularly, but remains under control of the autonomic nervous system Found in most hollow viscera . MULTI-UNIT SMOOTH MUSCLE Found in the eye and some other locations Does NOT activate spontaneously SKELETAL MUSCLE ORGANIZATION - Each muscle is a bundle of fibers - Each fiber is a long, multinucleated single cell - Each fiber is surrounded by a SARCOLEMMA- the cell membrane - There are NO SYNCYTIAL BRIDGES between the cells. When one cell goes off, the others don’t follow. TRANSVERSE TUBULES: T-tubules, invaginations of SARCOLEMMA: the muscle cell membrane the sarcolemma, they form part of the T-system; the space inside is an extension of the extracellular space. A single muscle fiber: one long cell, a tube of cytoplasm with holes in it. The holes are T-tubules; wells which lead down into the T-system. Inside, each mucle fibre contains myofibrils which are surrounded by sarcoplasmic reticulum. Myofibrils are separated by mitochondria. Several nuclei float around the place. SARCOPLASMIC RETICULUM: internal double layer of membrane which contains calcium. TERMINAL CISTERNS: these are enlargements of the sarcoplasmic reticulum which are in close contact with the T-system. They are found at the junctions of the A and I bands of the myofibril. MYOFIBRIL: the basic contractile element of a muscle cell; each is further divisible into individual filaments. The main proteins contained therein are myosin-II, tropomyosin, troponin, and actin. The myofilaments are STRIATED. This document was created by Alex Yartsev ([email protected]); if I have used your data or images and forgot to reference you, please email me. SKELETAL MUSCLE STRIATIONS A, H and M are dark striations; I and Z are light. A band: myosin I band: actin This pattern is produced by the orderly arrangement of actin, myosin, and all the other proteins. - myosin makes up the THIN FILAMENTS, which form the A bands - actin makes up the THICK FILAMENTS which form the less densely-staining I bands - The H-band is the area where the thick and H band SARCOMERE: thin filaments don’t overlap: only relaxed M line Area between two Z line muscle has H bands adjacent Z lines - The Z lines allow anchoring of the thin actin filaments - A crossection of the A band would reveal each thick myosin filament to be surrounded by 6 thin actin filaments in a precise hexagonal pattern Thin filaments: actin A band: myosin Thickmyosin filaments: myosin - each thick filament holds hundreds of myosin molecules - each myosin molecule has two globular heads 9in contact with actin) and a long tail ( all the tails meet at the M line) - the heads contain an actin-binding site and an ATP-hydrolysing site - The thin filaments are made of helical actin molecules, with tropomyosin wrapped around them, and troponin embedded along them. - The troponin molecule has 3 subunits: o Troponin T binds the troponin complex to the tropomyosin o Troponin I inihibits the interaction of myosin and actin o Troponin C contains the calcium-binding site OTHER PROTEINS OF NOTE include Dystrophin: o Dystrophin acts as a scaffold protein, connecting the myofibrils to the sarcolemma membrane. Basically, it gives the muscle fibers their shape and strength. o Muscular dystrophies are disorders resulting from an abnormal dystrophin architecture. The dystrophin gene is among the largest genes in the body. o Duchenne muscular dystrophy is caused by a complete absence of the protein This document was created by Alex Yartsev ([email protected]); if I have used your data or images and forgot to reference you, please email me. ELECTRICAL PHENOMENA IN SKELETAL MUSCLE - RESTING MEMBRANE POTENTIAL OF A MUSCLE CELL IS ABOUT -90mV - Action potentials are conducted along the muscle fiber at about 5 metres per second - After-polarization is relatively prolonged INSIDE THE MUSCLE CELL: concentrations in mmol/L - 12mmol Na+ - 155 mmol K+ - 3.8 mmol Cl- - 8 mmol HCO3- - 155 mmol organic anions, i.e. phosphates and proteins IN THE ECF: - 145 mmol Na+ - 4 mmol K+ - 120 mmol Cl- - 27 mmol HCO3- - 0 mmol anionic proteins THE EQUILIBRIUM POTENTIALS: - Na+ +65 mV - K+ -95 mV - Cl- -90mV - HCO3- - 32 mV CONTRACTILITY IN SKELETAL MUSCLE - A “muscle twitch” is a single action potential which causes a single contraction - The twitch happens about 2 ms after the start of membrane depolarization - FAST muscle fibers have a twitch duration as fast as 7.5 milliseconds - SLOW muscle fibers have a twitch duration about 100ms - The contraction itself is caused by the thick and thin filaments sliding over each other - The width of the A bands is constant; Z-lines move closer together MECHANISM OF CONTRACTION - At rest, tropinin I covers the site where actin and myosin interact. - At rest, the myosin heads is tightly bound to ADP When the muscle membrane depolarizes, there is suddenly tons of Ca++ in the cytosol: - the Ca++ binds to Troponin C - this weakens the bond between troponin-I and actin; releasing the actin binding site - The myosin head and the actin binding site form a cross-bridge - When the cross-bridge is formed, ADP is released from the myosin head - THE RELEASE OF ADP CAUSES A CONFORMATIONL CHANGE IN THE MYOSIN HEAD: The head moves, pulling the actin filament. This is the “power stroke”. - ATP quickly binds to the myosin head and this causes it to release the actin filament; the cross-bridge is broken - The myosin head quickly hydrolyses the ATP into ADP; this causes the head to return to normal shape, ready to stroke again. - As long as there is enough calcium and enough\ ATP, the cycle continues - Each power stroke shortens the sarcomere by about 10 nm - Each thick filament has about 500 myosin heads, and each head cycles about 5 times per second - This document was created by Alex Yartsev ([email protected]); if I have used your data or images and forgot to reference you, please email me. - EXCITATION-CONTRACTION COUPLING Action potential T Tubule Sarcoplasmic reticulum: terminal cistern ADP ATP Ryanodine Dihydropyridine SERCA receptor receptor pump Ryanodine receptor Ca++ Ca++ Muscle contraction occurs because excess calcium is pouring out of the sarcoplasmic reticulum Myofibril - That is the name we give to the process by which depolarization of the muscle fiber initiates contraction - The action potential travels down into the middle of the muscle fiber via the T-system - Depolarization of the T-tubule membrane causes activation of the DIHYDROPYRIDINE receptors, so named after the drug which blocks them . In the heart, the dihydropyridine receptor causes Ca++ release which then triggers the ryanodine receptor (which is a calcum-gated calcium channel) . In skeletal muscle, the dihydropyridine receptor binds directly to the ryanodine receptor. When the action potential reaches the dihydropyridine receptor, it causes the ryanodine receptor to open. - The ryanodine receptor is a calcium channel, and when triggered, it causes the release of Ca++ from the terminal cisterns of the sarcoplasmic reticulum. - This release of Ca++ triggers other ryanodine receptors and more Ca++ is released (Calcium-gated calcium release) - The excess calcium is pumped out of the cytosol back into the sarcoplasmic reticulum by the SERCA pump (sarcoplasmic or endoplasmic reticulum calcium ATPase) NOTE: ATP is required for actin-myosin contractions AS WELL AS for relaxation (it powers the SERCA pump) Types of contractions - ISOMETRIC: same length; the muscle doesn’t shorten appreciably - ISOTONIC: contraction against a constant load with decrease in muscle length - Isotonic contractions do useful work, while isometric ones don’t (because work is the product of force times distance) - This document was created by Alex Yartsev ([email protected]); if I have used your data or images and forgot to reference you, please email me. SUMMATION OF CONTRACTIONS - The contractile mechanism does not have a refractory period; re-stimulation of an ongoing contraction will produce another contraction on top of the existing one. - With rapidly repeated stimulation, activation of the contractile response occurs repeated before any relaxation has occurred - This constant contraction is called a TETANIC CONTRACTION - COMPLETE TETANUS = no relaxation at all - INCOMPLETE TETANUS = periods of incomplete relaxation take place between periods of contraction - During complete tetanus, the tension developed is about 4 times the tension of individual twitch contractions HOW OFTEN MUST I STIMULATE THE MUSCLE TO GET TETANUS?