Skeletal Muscle 2024 Handout PDF

Muscle physiology  Sugested reading Silverthorn 8e 375-395 Introduction and 12.1 Pay particular attention to Figs 12.3, 12.5,12.8, 12.9, 12.10 – These describe mechanism  Outline Types of muscle – Skeletal muscle, cardiac muscle, smooth muscle Ske...

Muscle physiology  Sugested reading Silverthorn 8e 375-395 Introduction and 12.1 Pay particular attention to Figs 12.3, 12.5,12.8, 12.9, 12.10 – These describe mechanism  Outline Types of muscle – Skeletal muscle, cardiac muscle, smooth muscle Skeletal muscle – Structure-function aspects of skeletal muscle Synapse (NMJ) Fine structure of muscle, myofibrils Ca++ binding Utilization of ATP Excitation contraction coupling Putting all together – Energy use – Generation of tension – Types of Muscle Fibres (skeletal muscle)  Types of muscle Three types of muscle – Skeletal muscle Make up muscular system – Cardiac muscle Found only in the heart – Smooth muscle Appears throughout the body systems as components of hollow organs and tubes Classified in two different ways – Striated or unstriated (much better) – Voluntary or involuntary (a) Skeletal muscle Skeletal muscle Nucleus multinucleated Muscle fiber striated (cell) Striations long, stacked in parallel (b) Cardiac muscle Striations Cardiac muscle Muscle fiber uninucleated striated Intercalated disk stacked end to end Nucleus intercalated disk (c) Smooth muscle Muscle fiber Smooth muscle uninucleated Nucleus not striated sheets or tubes  Muscle Controlled muscle contraction allows – Movement of joints, limbs, specific organs, and whole body – Propulsion of contents through various hollow internal organs – Emptying of contents of certain organs to external environment Skeletal muscle Neuronal control of skeletal muscle Controlled by neurons the CNS (brain and spinal cord) Two neuron chain: – Upper Motor Neurons with cell body in the primary motor cortex synapse on lower motor neurons in the spinal cord – Lower Motor neurons with cell body in spinal cord send axons to synapse on muscle cells The group of muscle cells controlled by a lower motor neuron is a motor unit  Primary motor cortex Neurons in the primary motor cortex send axons through white matter in brain Axons descend through midbrain and medulla Cranial nerves to selected MIDBRAIN About 90% of axons cross over at the “Medullary pryamids” skeletal muscles MEDULLA OBLONGATA Motor neurons send axons out the ventral roots and make synapses on muscle cells Pyramids Somatic motor Nerve-muscle synapse is neurons to skeletal muscles SPINAL CORD called neuromuscular junction (NMJ) Fig 13-11 The motor unit Each muscle is composed of a large number of muscle cells. In mammals, each muscle cell receives ONLY ONE synapse. The motor unit is one motorneuron and all of the muscle cells it innervates Sometimes a motor neuron will innervate only one muscle cell, sometimes many. The NMJ is a special synapse 1. The synapse between the lower motor neurons and muscle cell is called the neuromuscular junction (NMJ) 2. The NMJ is HUGE (1000- 10,000 μm2) vs a central synapse (0.05 μm2) 3. The postsynaptic membrane is folded and has a high density of nAChR (hundreds of thousands!!) Central synapse vs NMJ Not to scale!!!!! nAChR VG Na+ channels Principles of Neural Science, 8th ed Principles of Neural Science, 8th ed  The NMJ is a special synapse 1. The synapse is HUGE (1000-10,000 μm2) vs a central synapse (0.05 μm2) 2. The postsynaptic membrane is folded and has a very high density of nAChR (hundreds of thousands!!) 3. The EPSP in muscle cell is large (30-50 mV), whereas the EPSP at a central synapse may be 0.5-1 mV A lot of ACh binding to a lot of nAChR 4. Very high density of VG Na+ channels within the post synaptic folds 5. The result of the above four points is that a single AP in a motor neuron will always cause an AP in the postsynaptic muscle cell (no summation of EPSP). Structure of skeletal muscle Structure of Skeletal Muscle A muscle consists a number of muscle fibers lying parallel to one another and held together by connective tissue Single skeletal muscle cell is known as a muscle fiber – Multinucleated – Large, elongated, and cylindrically shaped – Fibers usually extend entire length of muscle Figure 12.3a-1 ANATOMY SUMMARY – Skeletal Muscles Skeletal muscle Tendon Nerve and blood vessels Connective tissue Muscle fascicle: bundle of fibers Connective tissue Nucleus Muscle fiber  Ultrastructure of a muscle cell Mitochondria Sarcoplasmic reticulum Nucleus Thick Thin filament filament T-tubules Myofibril Sarcolemma A band Sarcomere Z disk Z disk Myofibril M line I band H zone Figure 12.3b-c ANATOMY SUMMARY – Skeletal Muscles  Sarcomere Z-line A band A band A band A band I band I band I band H zone M-line Structure of the myofibril Actin, myosin, titin Thick Filaments: Myosin Major component of thick filament Protein molecule consisting of two identical subunits shaped like a golf club – Tail ends are intertwined around each other – Globular heads project out at one end Thick Filaments: Myosin Tails oriented toward center of filament and globular heads protrude outward at regular intervals – Heads **form cross bridges** between thick and thin filaments – Myosin head has two important sites critical to contractile process An actin-binding site A myosin ATPase  Thin Filaments: Actin, tropomyosin troponin, nebulin, titin Actin Primary structural component Thin filaments of thin filaments G-actin monomers are Titin spherical, but assemble into long chains Troponin Nebulin Each actin molecule has a special binding site for attachment with myosin head Tropomyosin G-actin molecule – Binding results cross bridge Actin chain formation  Thin Filaments: Actin, tropomyosin troponin, nebulin, titin Tropomyosin and troponin Thin filaments Regulatory proteins Tropomyosin Titin – Thread-like molecules that interacts with actin along its spiral groove Troponin Nebulin – Tropomyosin covers myosin binding sites Tropomyosin G-actin molecule Actin chain  Thin Filaments: actin, tropomyosin troponin, nebulin, titin Troponin and tropomyosin Troponin Thin filaments – Made of three subunits One binds to tropomyosin One binds to actin One can bind with Ca2+ Titin – When not bound to Ca2+, troponin stabilizes tropomyosin in blocking position over actin’s cross-bridge Troponin Nebulin binding sites – When Ca2+ binds to troponin, tropomyosin moves away from blocking position Tropomyosin G-actin molecule – With tropomyosin out of way, actin and myosin bind, interact at cross- Actin chain bridges – Cross bridge formation Titin and nebulin Titin – Giant, elastic protein – Joins M-lines to Z lines at opposite ends of sarcomere – Two important roles: Helps stabilize position of thick filaments in relation to thin filaments Improves muscle’s elasticity Nebulin – Aligns actin filaments Myomesin – M-line Muscle shortens when actin and myosin slide past each other (sliding filament hypothesis) Figure 12.8 TROPONIN AND TROPOMYOSIN Relaxed state. Myosin head cocked. Initiation of contraction. A calcium signal Myosin is weakly bound to actin. Tropomyosin initiates contraction. partially blocks binding site on actin. Cytosolic Ca2+ Ca2+ levels increase in cytosol. Troponin G-actin Tropomyosin shifts, exposing binding site on actin. Ca2+ binds to troponin (TN). Troponin-Ca2+ TN TN complex pulls Myosin head Actin tropomyosin Tropomyosin moves away from actin’s ADP myosin-binding site. ADP Pi Power stroke Pi Myosin binds strongly to actin and completes power stroke. Actin filament moves. Fig. 8-9, p. 260  Actin and myosin DO NOT CONTRACT. Myosin is properly called a motor protein: a protein that hydrolyzes ATP to convert chemical energy to carry out mechanical work Fig. 8-9, p. 260 Utilization of ATP Figure 12.9 THE CONTRACTION CYCLE Tight Binding in the Rigor State G-actin molecule Myosin binding sites ATP binds to myosin. Myosin filament Myosin releases actin. ADP ATP binds. releases. Myosin releases ADP at the Myosin hydrolyzes ATP. Energy end of the power stroke. Contraction- relaxation from ATP rotates the myosin head to the cocked position. Myosin The Power Stroke binds weakly to actin. Actin filament moves Sliding filament toward M line. Head Ca2+ ADP swivels. signal Pi ADP and Pi Power stroke remain bound. Myosin begins when releases Pi. tropomyosin moves off the binding site. Excitation-contraction coupling How action potentials in muscle stimulate contraction  Mitochondria Sarcoplasmic reticulum Nucleus Thick Thin filament filament T-tubules Sarcolemma Myofibril Figure 12.3b ANATOMY SUMMARY – Skeletal Muscles  Sarcoplasmic reticulum Muscle cells have extensive network of endoplasmic reticulum: sarcoplasmic reticulum (SR) SR has very high Ca++ concentration SR has a powerful Ca++ ATPase transporter – Uses ATP to pump Ca++ from cytoplasm into SR SR also has a Ca++ binding protein called Calsequestrin. – Helps maintain high Ca++ concentration Mitochondria Sarcoplasmic reticulum Nucleus Thick Thin filament filament T-tubules Sarcolemma Myofibril  T-tubules T-tubules run perpendicular from surface of muscle cell membrane into central portions of the muscle fiber T-tubules aligned on the edges of the A band (thick filaments, myosin) Mitochondria Sarcoplasmic reticulum Nucleus Thick Thin filament filament T-tubules Sarcolemma Myofibril  T-tubules T-tubule is continuous with surface T-tubule brings action Thin filament membrane – action potentials into interior of muscle fiber. Sarcolemma Thick filament potential on surface membrane also invade T-tubule Spread of action potential down a T tubule triggers release of Ca2+ from Triad Sarcoplasmic reticulum stores Ca2+ Terminal cisterna sarcoplasmic reticulum into cytosol Fig 12-4  Voltage gated Ca++ channel (=dihydropyridine receptor) T-tubule Ryanodine receptor Ca++ release channel Sarcoplasmic reticulum Put it all together (this is very important) 1. An AP invades the presynaptic terminal and causes release of ACh 2. ACh binds to the receptor, allows entry of Na+, causes EPSP large enough to trigger an AP 3. The AP invades the T-tubule system 4. The AP causes the DHP receptor to open, and in turn, open the RyR channel. This causes a massive release of Ca++, and increase in intercellular Ca++ concentration 5. Ca++ binds troponin. Troponin pulls tropomyosin away from the myosin binding site on the actin protein 6. Power stroke 7. Actin filaments slide towards centre of the sarcomere 8. Free Ca++ pumped back into SR  Rigor Mortis ~3-4 hours after death, peak at ~12 hours After death, intracellular Ca++ rises (leaks out of SR) Ca++ allows troponin-tropomysin complex to move aside and allow myosin cross bridges to bind to actin. But…. – ATP is needed to separate myosin from actin. – Dead cells don’t produce more ATP. – So once bound, cross bridges can’t detach. Rigor mortis subsides when enzymes start to break down myosin heads  Relaxation of muscle Action potentials stop arriving at NMJ ACh dissociates from AChR, gets degraded Ca++ ATPase pumps free Ca++ back into SR Ca++ dissociates from troponin , pumped back into SR Tropomyosin moves back into position, blocking cross bridge binding site Muscle ceases to maintain tension Actin and myosin slip past each other – Pulled by titin – Pulled by antagonistic muscle Energy use in muscle Key Steps in the Contraction-Relaxation process that Require ATP 1. Splitting of ATP by myosin ATPase for power stroke 2. Active transport of Ca2+ back into sarcoplasmic reticulum 3. Na+/K+ ATPase  Main Energy Sources for Muscle Contraction 1. Stored ATP (very little stored) 2. Creatine phosphate First energy sourced tapped at onset of contractile activity after stored ATP exhausted 3. Oxidative phosphorylation Takes place within muscle mitochondria if sufficient O2 is present 4. Glycolysis Supports anaerobic or high-intensity exercise  Creatine phosphate During times of rest when ATP demand is low, muscle stores energy in the form of creatine phosphate First store of energy tapped to fuel muscle contraction. Provides 4-5 times the energy of stored ATP Limited supply (only a few minutes)  Creatine phosphate Creatine Kinase P P P P P ADP ATP + + Creatine Phosphate P Creatine  Creatine phosphate Stores a high energy phosphate Creatine Kinase P P P P P ADP ATP + + Creatine Phosphate P Creatine At rest:  Creatine phosphate Produces ATP that can be used for muscle contractions Creatine Kinase P P P P P ADP ATP + + Creatine Phosphate P Creatine During first few minutes of exercise  Oxidative phosphorylation The process that provides energy during light to moderate exercise – Uses stores of glycogen in muscle (30 min) – Good yield of ATP – Aerobic exercise – Adequate supply of oxygen To maintain adequate oxygen – Increase ventilation – Increase heart rate and force of contraction – Dilate skeletal blood vessels  Anaerobic Glycolysis Primary source of ATP when oxygen supply is limited (during intense exercise) Rapid supply of ATP – Only a few enzymes involved Very low ATP yield – Only 2 per glucose molecule – Lactic acid, acidifies muscle and contributes to fatigue Duration of anaerobic glycolysis is limited  What causes muscle fatigue? Central fatigue – Psychological Peripheral – Decrease in release of ACh – Receptor desensitization – Changes in of muscle RMP – Impaired Ca++ release by SR – Intracellular pH of muscle – Damage to muscle cells – Others…. https://www.joionline.net/trending/content/exercise-fatigue Generation of tension Muscle fiber +30 Action potential Neuron from CNS membrane potential in mV -70 Motor Recording Time end plate electrodes 2 ms Axon +30 synaptic terminal Muscle fiber delay membrane Muscle action potential potential in mV -70 Time Latent Contraction Relaxation period phase phase (5-10ms) Development Tension of tension during one muscle twitch 10–100 msec Time Fig 12.16 ***** **The most force a motor unit can generate**  Takes several AP to cause generation of maximal tension Some think it takes several APs to increase intracellular Ca++ enough to saturate actin’s myosin binding sites Some think intracellular Ca++ reaches its maximum (saturates) after first action potential. – Takes time for Ca++ to interact with troponin, and for cross bridges to form Length-tension Figure 12.15 Adapted from A. M. Gordon et al., J Physiol 184: 170–192, 1966. LENGTH-TENSION RELATIONSHIPS Too much or too little overlap of thick and thin filaments in resting muscle results in decreased tension. C B D 100 Tension (percent of maximum) 80 60 40 A E 20 0 1.3  m 2.0  m 2.3  m 3.7  m Decreased Increased length length Optimal resting length Types of skeletal muscle fibres (=types of motor units)  Types of muscle fibres In turkey and chicken, fibre types are grouped together (white meat, dark meat). In mammals, fibre types are interspersed Most mammals (including humans) have 3 types of motor units – Slow twitch oxidative (=red muscle) – Fast twitch oxidative-glycolytic (=red muscle) – Fast twitch glycolytic (=white muscle)  Three Types of Muscle Fibres 1. Slow twitch oxidative (slow fatigue resistant) Small fibres Small amounts of tension, slowly Capable generating tension for long periods of time without running down energy stores Large numbers of mitochondria Well vascularized, Myoglobin (to facilitate oxygen transfer from blood) 2. Fast oxidative-glycolytic (fast fatigue resistant) Fibres are larger than slow twitch Generate a lot of tension, moderately fast Somewhat resistant to fatigue Moderate # of mitochondria  Types of muscle fibres 1. Gvhg 2. kkj 3. Fast twitch glycolytic (fast fatigable) Largest fibres White muscle (little myoglobin) Generate the most tension Fatigue rapidly Few mitochondria (Anaerobic catabolism) Back to this experimental setup…. Muscle fiber +30 Action potential Neuron from CNS membrane potential in mV -70 Motor Recording Time end plate electrodes Axon +30 terminal Muscle fiber membrane Muscle action potential potential in mV -70 2 msec Time Latent Contraction Relaxation period phase phase Tension Development of tension during one muscle twitch 10–100 msec Time  50 ms 25 ms 25 ms Principles of Neural Science, Fourth ed, (2000) Kandel Schwartz Jessell All muscle fibres within the same motor unit are of the same type In mammalian muscles, different fibre types may coexist side by side But all muscle fibres within the same motor unit are of the same type  Recruitment of motor units First Motor units recruited: – Smallest motor neurons – Slow twitch fatigue resistant (red; oxidative) – Each motor unit has only a few fibres Next recruited – These motor neurons are slightly larger – Motor units that include fast fatigue resistant fibres Last recruited – Fast fatigable (= fast twitch glycolytic, white muscle) – The largest motor neurons, motor unit contains the most fibres Size principle: easier to bring a small neuron to threshold than a large neuron