Skeletal Muscle Physiology Presented by Ifeoma Ezeonyebuchi 1

Skeletal Muscle Physiology Presented by Ifeoma Ezeonyebuchi 1

Objectives • Explain how muscle fibers are stimulated to contract by describing events that occur at the neuromuscular junction • Describe how an action potential is generated • Follow the events of excitation-contraction coupling that lead to cross bridge activity 2

For muscle to contract… • Must be activated stimulated by nerve ending • Must generate and propagate action potential along its sarcolemma • Short lived rise in intracellular Ca 2+ levels that is the final trigger for contraction must occur 3

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Nerve Stimulus and Events at the NMJ • Somatic motor neurons nerve cells that activate skeletal muscle fibers • Begin the brain • Axons leave CNS and travel to appropriate muscle • Neuromuscular Junction (NMJ) where the nerve meets the muscle • Synaptic cleft space between nerve and muscle • Each muscle fiber only has one NMJ • Synaptic vesicles contain Acetylcholine (ACh) • The neurotransmitter at the NMJ • Junctional folds highly folded “trough” of the sarcolemma • Increase surface area for ACh receptors 5

• When action potential of a somatic motor neuron reaches the axon terminal, voltage gated Ca 2+ channels open causing synaptic vesicles to release ACh into the synapse • ACh diffuses across the synaptic cleft and binds to ACh receptors on the muscle fiber • Electrical events are triggered that lead to an action potential of the muscle fiber • ACh is cleared from synapse by aceytlcholinesterase (AChase), an enzyme that breaks down ACh • ACh remaining on the receptors would cause continuous contraction 6

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Myasthenia Gravis • Generalized muscle weakness • Occurs because of shortage of ACh receptors • Autoimmune disorder 8

Generation of Action Potential at the Sarcolemma • Resting sarcolemma is polarized • 3 steps • 1. Local depolarization and generation of end plate potential • Binding of ACh molecules to receptors at the NMJ opens ligand gated ion channels • Channels allow Na+ and K+ to pass • More Na+ diffuses in than K+ diffusing out change in membrane potential as inside of sarcolemma becomes slightly positive = depolarization 9

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• 2. Generation and propagation of action potential • End plate potential the initial local depolarization • End plate potential spreads in all directions and becomes an action potential • End plate potential spreads to adjacent membrane areas and opens voltage-gated Na+ channels • Na+ enters • Action potential begins once membrane voltage reaches its threshold • Action potential is propagated (moves along) the sarcolemma opening more voltage gated Na+ channels • Once an action potential starts it can’t be stopped 11

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• 3. Repolarization • Sarcolemma restored to its initial polarized state • Na+ channels close and voltage gated K+ channels open • K+ rapidly diffuses out of the muscle fiber, therefore restoring negative charge conditions inside the sarcolemma • Refractory period muscle fiber is unable to be stimulated until repolarization is complete • Repolarization only restores the electrical gradient • Na+/K+ ATP pump restores the ionic gradient 13

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Excitation-Contraction (EC) Coupling • EC coupling is the sequence of events by which transmission of an action potential along the sarcolemma leads to the sliding of the myofilaments • Action potential is brief and ends before muscle contraction occurs • EC coupling occurs during latent period time between the action potential and the beginning of the contraction 16

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Muscle Fiber Contraction: Cross. Bridge Activity • Action potential of sarcolemma spreads to the T-tubules • Voltage-sensitive proteins of the T-tubules change shape • Change in shape stimulates sarcoplasmic reticulum to release Ca 2+ into the cytosol • As Ca 2+ levels rise, the Ca 2+ binds to regulatory sites on troponin • Each troponin must bind 2 Ca 2+ ions to in order to change shape and move tropomyosin out of the way • Once myosin-binding sites are available events of the crossbridge cycle occur quickly 18

• Sliding of thin filaments continues as long as Ca 2+ and ATP are available • SR pumps back Ca 2+, troponin regains shape and tropomyosin blocks myosin-binding sites relaxation 19

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Cross-Bridge Cycle • Requires ATP in order for myosin to detach from actin • Refer to following diagram for details 21

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Rigor Mortis • Muscle rigidity after death • Dying cells are unable to exclude Ca 2+ from extracellular environment, so Ca 2+ enters the muscle cell allowing myosin to bind to actin • ATP synthesis stops after breathing ceases • ATP is no longer available to cause myosin to detach from actin muscle maintains contraction • Eventually goes away after muscle proteins begin to breakdown 23

Principles of Muscle Mechanics • The principles governing contraction of a single muscle fiber and of skeletal muscle consisting of a large number of fibers is the same • Muscle tension the force exerted by a contracting muscle on an object • Load the opposing force exerted on the muscle by the weight of the object to be moved 24

• Isometric contraction muscle tension is developed but load does not move • Lifting a 2, 000 lb car • Isotonic contraction muscle tension developed overcomes load and muscle shortens • Lifting 5 lb weight • Skeletal muscle contracts with varying force and for different periods of time in response to stimuli of varying frequencies and intensities 25

Motor Unit • Nerve-muscle functional unit • Each muscle is served by at least one motor nerve • Each motor nerve contains hundreds of axons of motor neurons • As an axon enters a muscle it branches into a number of terminals, each forming a neuromuscular junction with a muscle fiber • Motor unit = motor neuron and all the muscle fibers it serves 26

• Number of muscle fibers per motor unit varies • Can be as low as four as high as hundreds • Fine motor control small motor units • Fingers, eyes, etc. • Large, weight-bearing muscle large motor units • Requires less precise movement • A motor neuron can serve several muscle fibers but a muscle fiber can only be served by one motor neuron 27

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Muscle Twitch • Response of a motor unit to a single action potential of its motor neuron • Myogram graphic recording of contractile activity • Each twitch myogram has 3 distinct phases • Latent period • Period of contraction • Period of relaxation 29

Latent Period • First few milliseconds after stimulation when excitationcontraction coupling is happening • Muscle tension is beginning to increase but no response is seen on the myogram 30

Period of Contraction • • Cross-bridges are active Myogram tracing rises to a peak Lasts for 10 -100 ms Differences in times of how quickly and how long a muscle contracts is due metabolic differences of the myofibrils 31

Period of Relaxation • Lasts for 10 -100 ms • Initiated by Ca 2+ reentry into the SR • Muscle tension decreases to zero 32

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Grades Muscle Responses • The variations in muscle contraction needed for proper control of skeletal movement • Muscle contraction can be graded by either • Changing the FREQUENCY of stimulation OR • Changing the STRENGTH of stimulation 35

Changes in Frequency • The nervous system achieves greater muscular force by increasing firing rate of motor neurons • Example: If 2 identical stimuli are delivered to a muscle in rapid succession, the second twitch will be stronger than the first • On the myogram: the second twitch will appear to ride on the shoulders of the first • Temporal (wave) summation when second contraction occurs before muscle completely relaxes • 2 nd contraction is stronger because the muscle is already partially contracted from the 1 st stimulation • Refractory period is still honored; if 2 nd stimulus is given before repolarization is complete no wave summation will happen 36

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• If the muscle is stimulated at an increasingly faster rate… • Relaxation time between twitches gets shorter and shorter • Concentration of Ca 2+ in cytosol increases • Degree of wave summation becomes greater and greater • Unfused (incomplete) tetanus sustained, quivering contraction • Fused (complete) tetanus evidence of muscle relaxation disappears and contractions fuse into smooth, sustained contraction plateau • Muscle fatigue occurs after continuous muscle contraction. Muscle becomes unable to contract and tension drops to zero 38

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Changes in Strength • Recruitment = multiple motor unit summation more motor units involved in muscle contraction • Controls force of contraction more precisely than wave summation • In the lab this happens by delivering shocks of increasing voltage (not rate) to the muscle • Subthreshold stimuli that produces no observable contraction • Threshold stimulus at which first observable contraction occurs • Maximal Stimulus the strongest stimulus that produces increased contractile force • Point at which all muscle motor units are recruited • Increasing stimulus beyond maximal stimulus will not produce a stronger contraction 41

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Recruitment Process • Not random • Size Principle motor units with the smallest muscle fibers are recruited first. Motor units with increasingly larger muscle fibers are then recruited • Smallest muscle fibers are controlled by highly excitable (low threshold) motor neurons which get activated first • Larger muscles are controlled by the largest, least excitable (high threshold) neurons and are activated only when the most powerful contraction is needed 43

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Muscle Tone • Relaxed muscles are always slightly contracted • Due to spinal reflexes that activate first one group of motor units and then another in response to activation of stretch receptors in the muscles • Does not produce active movement • Keeps muscles firm, healthy and ready to respond to stimulation 45

Isotonic Contractions • Muscle length changes and moves load • 2 types • Concentric contractions muscle shortens and does work • Example: picking up a book • Eccentric contractions muscle generates force as it lengthens • Example: calf muscles as you walk up a hill • 50% more forceful than concentric contractions • More often cause delay-onset muscle soreness (day after you walk up the hill) • Example: Bicep curl 46

Isometric Contraction • Tension without change in muscle length • Occurs when one tries to move a load that creates a force greater than the maximal tension 47

Muscle Metabolism • ATP needed to cross-bridge movement and detachment and operation of Calcium pump at the SR • Muscle only stores 4 -6 seconds worth of ATP • After ATP is hydrolyzed to ADP and inorganic phosphate (Pi) it is quickly regenerated • Direct phosphorylation of ADP by creatine phosphate • Anaerobic pathway of glycolysis (glucose lactic acid) • Aerobic respiration 48

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Direct Phosphorylation • • ADP phosphorylated by creatine phosphate Creatine phosphate high energy molecule stored in muscle Transfers phosphate group to ADP Enzyme: creatine kinase • • Reversible reaction Does not require oxygen Each creatine phosphate provides 1 ATP Provides 15 seconds worth of energy (along with ATP stores) 50

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Anaerobic Pathway • “Kicks in” as stored ATP and creatine phosphate stores are depleted • Glycolysis first phase of glucose breakdown • Glucose pyruvic acid (via glycolysis) • 2 ATP molecules produced • Vigorous exercise = increased muscle contraction= bulging muscle = impaired blood flow and oxygen delivery • Anaerobic means “without oxygen” so this process does not involve oxygen • Lack of oxygen cause pyruvic acid lactic acid • Lactic acid reenters bloodstream • Anaerobic glycolysis provides ~60 seconds of energy (along with ATP and CP stores) 52

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Aerobic Respiration • • Provides 95% of ATP during light to moderate exercise Occurs in mitochondria Requires oxygen Glucose still converted to pyruvic acid • In presence of oxygen, pyruvic acid undergoes series of chemical reactions (Krebs/Citric Acid cycle) to eventually produce much more ATP • Uses additional energy sources to yield ATP (fatty acids, amino acids) • Slow process but large yield (~32 ATP molecules per 1 glucose) • Provides hours of energy • Overall reaction: Glucose + oxygen CO 2 + water + ATP 54

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Force of Muscle Contraction • Influenced by • • Number of muscle fibers stimulated Relative size of the fibers Frequency of stimulation Degree of muscle stretch 57

Number of Muscle Fibers Stimulated • The more motor units recruited the greater the muscle force 58

Size of Muscle Fibers • The greater the cross-sectional area of muscle (bulk) the more tension that can develop • More tension = more strength • Hypertrophy = increase in muscle size • Resistance training can cause hypertrophy 59

Frequency of Stimulation • Remember summation • Summation leads to stronger contraction 60

Degree of Muscle Stretch • Ideal length-tension relationship: occurs when muscle is slightly stretched and thin and thick filaments overlap optimally • This ideal relationship allows sliding along the entire length of the thin filaments • Reason why athletes stretch before playing • However, overstretching may cause a lack of a overlap and myosin heads won’t have anything to grasp onto 61

Velocity and Duration of Contraction • Muscles vary in how fast they can contract and how long they continue to contract before they fatigue • Influenced by muscle fiber type, load and recruitment 62

Muscle Fiber Type • Classified by: • Speed of contraction: fast fibers and slow fibers • Speed depends on how fast their ATPases split ATP • Major pathways forming ATP • Oxidative fibers depend on oxygen (aerobic) • Glycolytic fibers depend on anaerobic glycolysis • Slow oxidative fibers best for endurance activities • Fast glycolytic fibers best for short-term rapid movements 63

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