L13 Skeletal Muscle II PDF

IBSSD 1525 2024-25 Erin Stephenson, Ph.D. [email protected] L13: Skeletal Muscle II: Contraction READING: Moore’s Essential Cli...

IBSSD 1525 2024-25 Erin Stephenson, Ph.D. [email protected] L13: Skeletal Muscle II: Contraction READING: Moore’s Essential Clinical Anatomy, 7th ed, Agur & Dalley, 2024: Sections: Muscular System Essential Physiology for Dental Students, Ali & Prabhakar, 2019: Sections: 3 Muscle Physiology, 4 Heart OBJECTIVES: At the end of this class, students should be able to: Diagram the structure of a sarcomere and discuss the relationship of the sarcomere to myofilaments Explain the sliding filament model of contraction Describe the function of the sarcoplasmic reticulum in muscle contraction Describe the function of T-tubules in muscle contraction Describe the structures contributing to the neuromuscular junction Diagram and describe the steps involved in transmission of signals from motor neurons to myofibers Diagram and describe the process of cross bridge cycling Discuss the chemical requirements of cross bridge formation Explain the process of excitation-contraction coupling List and discuss factors that influence the force of muscle contraction List and discuss factors that influence contraction velocity I. Sarcomeres A. Contractile unit formed by overlapping myofilaments B. Give striated muscles its alternating light-dark appearance C. Outer boundary is the Z-disc 1. Region between two Z-discs is a sarcomere a. Z-discs connect each sarcomere end-to-end i. Multiple sarcomeres in series form a myofibril Many myofibrils within a sarcolemma form a myofiber  Like neurons, myofibers are excitable cells − Membrane potential changes in response to external cues D. Myofilaments 1. Thin filaments a. Actin i. Perpendicular projections from either side of the Z-disc I-band ii. Thin filament ends overlap the thick filaments 2. Thick filaments a. Myosin i. Runs parallel to thin myofilaments A-band  Joined centrally by a perpendicular M-line  Region where thick and thin myofilaments don’t overlap is the H-zone ii. Arranged as six polypeptide chains Two myosin heavy chains twist together to form a rod-like tail that extends into two globular heads extending from a hinge region  Globular heads contain actin and ATP binding sites Four myosin light chains  Two associated with each globular head © Dr. Erin Stephenson & MWU 2024 1  IBSSD 1525 2024-25 L13 Skeletal Muscle II 3. Thin filament regulatory proteins a. Tropomyosin i. Blocks myosin binding sites on actin when a myofiber is not contracting b. Troponin complex i. Three proteins Troponin-T  Attaches the troponin complex to tropomyosin Troponin-I  Works with tropomyosin to inhibit myosin binding Troponin-C  Binds Ca2+ to initiate contraction ii. Located at intervals along the tropomyosin filaments 4. Intermediate filaments a. Desmin i. Extends from Z-disc to connect adjacent myofibrils to one another 5. Structural proteins maintain sarcomere stability a. Titin i. Largest known protein ii. Titin springs extend between the M-line and Z-disc Spans half the length of the sarcomere iii. Facilitates sarcomere recoil after stretching iv. Stiffens as it uncoils to resist excessive stretch v. Contains binding sites for other muscle-associated proteins Loss-of-function TTN (the titin gene) variants result in various, often lethal myopathies b. Dystrophin i. Attaches the array of myofibrils to the sarcolemma Dystrophin-associated protein complex runs between actin myofilaments and the extracellular matrix (endomysium) ii. Provides mechanical stability and myofiber stiffness iii. Loss-of-function DMD (the dystrophin gene) variants results in Duchenne or Becker muscular dystrophies II. Sliding filament model A. During contraction thin filaments slide toward the M-line and increase their overlap of the thick filaments 1. Distance between Z-discs shortens but myofilaments do not change length a. I-bands shorten b. H-zones disappear c. A-bands remain the same length but A-bands of adjacent sarcomeres move closer together III. Sarcoplasmic reticulum and T-tubules A. Sarcoplasmic reticulum (SR) 1. Elaborate network of smooth endoplasmic reticulum surrounding each myofibril a. Terminal cisterns i. Run perpendicular to the myofibril, along the A-band-I-band junction b. Most SR tubules run longitudinally between terminal cisterns i. Communicate with one another around the H-zone 2. Regulates intracellular Ca2+ concentrations a. Ca2+ is the signal that triggers myofibers to contract B. T-tubules 1. Deep, elongated invaginations of sarcolemma at each A-band-I-band junction a. The T-tubule cavity (lumen) increases the surface area of a myofiber 2. Facilitates rapid penetration of changes in the membrane potential a. Action potential spread throughout the myofiber © Dr. Erin Stephenson and MWU 2024 2 IBSSD 1525 2024-25 L13 Skeletal Muscle II 3. Forms triads with flanking terminal cisterns a. T-tubule proximity to terminal cisterns promotes rapid release of Ca2+ when the membrane depolarizes IV. Motor neurons and the neuromuscular junction A. Motor unit 1. A motor neuron and all the myofibers it innervates B. Motor neurons 1. Deliver electrical signals from the CNS to the neuromuscular junction a. Action potentials are propagated along a neuron toward its axon terminals b. Electrical signal is converted to a chemical signal (neurotransmitter) in the axon terminal i. Action potentials can’t jump between cells Neurotransmitter must communicate instructions to depolarize to the myofiber ii. When an action potential reaches the axon terminal, voltage-gated Ca2+ channels open and Ca2+ enters the axon terminal iii. Ca2+ entry triggers exocytosis of neurotransmitter-containing vesicles C. Acetylcholine (ACh) 1. Neurotransmitter that induces myofiber depolarization a. Ca2+ entry into the axon terminal causes ACh release into the neuromuscular junction b. ACh binds nicotinic receptors on the motor end plate causing local depolarization i. Specialized region of sarcolemma adjacent to the synaptic cleft Comprised of junctional folds with a high density of cholinergic receptors ii. Upon binding of 2x ACh molecules, a non-selective cation channel in the nicotinic receptor opens to allow Na+ influx and K+ efflux across the motor end plate Generation of an end plate potential (EPP)  A type of graded potential (i.e., not all-or-none) localized to the motor end plate  Summation of multiple miniature EPPs is required to depolarize the sarcolemma past the threshold potential c. The EPP spreads into the sarcolemma and triggers an action potential i. Depolarization of T-tubules promotes Ca2+ release from SR ii. Ca2+ binds troponin-C and initiates contraction iii. ACh is degraded by acetylcholinesterase within the synaptic cleft Acetate and choline are recycled Prevents continued contraction V. Excitation-contraction coupling and cross bridge cycling A. Sequence of events by which transmission of an action potential along the sarcolemma causes myofilament sliding (see: Section II - Sliding filament model) B. Ca2+ released from the SR following an action potential binds troponin-C 1. The troponin complex changes shape 2. Tropomyosin moves into the groove of the actin helix a. The myosin binding sites become exposed C. High-energy myosin attaches to its binding site on actin 1. Cross bridge formation D. ADP and Pi are released and the myosin head pivots and bends 1. Power stroke E. The attached actin filament is pulled toward the M-line F. ATP attaches to low-energy myosin, detaching it from actin 1. Cross bridge detachment G. Hydrolysis of ATP on myosin occurs and returns myosin to its high energy state 1. Cocking of the myosin head H. The cycle repeats and the myosin heads will walk along the length of the actin filament 1. Sarcomere shortening I. Cross bridge cycling will only continue as long as sufficient Ca2+ and ATP are available © Dr. Erin Stephenson and MWU 2024 3 IBSSD 1525 2024-25 L13 Skeletal Muscle II 1. Ca pumps in the SR begin to reclaim the Ca that was released 2+ 2+ 2. Removal of Ca2+ from troponin-C returns the troponin complex to its resting shape a. Tropomyosin will return to blocking the myosin binding sites on the actin filaments b. Elastic fibers will recoil and the myofibril will return to its resting length VI. Force and velocity of muscle contraction A. When a motor neuron transmits an action potential, all fibers the motor neuron innervates contract 1. Fibers innervated by a single motor neuron are evenly distributed throughout the muscle a. Permits weak contraction of whole muscle if only one motor neuron is depolarized b. Recruitment of variable numbers of motor units/fibers = graded muscle contraction i. Facilitates controlled rather than jerky movements when a muscle contracts B. Force of contraction depends on the number of myosin cross bridges that are attached to actin 1. Factors that influence cross bridge formation – a. Frequency of stimulation i. The greater the frequency of stimulus, the greater the strength of contraction ii. Temporal summation Muscle tension increases with increasing action potential frequency  Relaxation time between contractions diminishes  Cytosolic Ca2+ concentrations increase and remain elevated − Recall, Ca2+ binds Troponin-C to move tropomyosin and expose myosin binding sites on actin and is thus required for cross bridge cycling  Summation of contractions occurs when maximal tension is reached − Maximal tension (i.e., fused tetanus) is where individual contractions are indistinguishable from one another o Fused tetanus rarely (if ever) occurs in life but possible experimentally − Although summation contributes to contractile force, its primary function is to recruit a specific number of fibers to facilitate smooth, continuous contraction (e.g., postural muscle tone) b. Number of motor units/fibers recruited i. The stronger the stimulus, the greater the number of motor units recruited More motor units recruited = stronger contraction Maximal stimulus represents the point where all motor units are recruited  Asynchronous recruitment more common − Allows fibers to recover while others contract c. Fiber cross sectional area i. Myofiber size is associated with contractile strength Smallest fibers are most excitable but have lowest capacity for force generation  Lowest threshold for contraction  Recruited early Largest myofibers are least excitable but have greatest capacity for force generation  Highest threshold for contraction  Only activated if the force of contraction requires it – late recruitment d. Degree of muscle stretch i. Length-tension relationship The amount of tension that can be generated is determined by fiber length  Sarcomeres closer to resting length have greater capacity for shortening − Increasing overlap between thick and thin filaments required for shortening − Excessive stretch leaves myosin heads with nothing to attach to − Excessive shortening overlaps thin filaments, blocking myosin heads e. Fiber arrangement i. Physiological cross-sectional area (review: L12) C. Rate of ATP hydrolysis by myosin determines the speed at which cross-bridge cycling can occur 1. Factors affecting contraction velocity - © Dr. Erin Stephenson and MWU 2024 4 IBSSD 1525 2024-25 L13 Skeletal Muscle II a. Properties of the innervating motor neuron i. Excitability, conduction velocity, cell diameter, etc. b. Fiber type (review: L15 Section IV) i. Rate at which myosin ATPase transforms ATP into ADP + Pi depends on isoform Slow fibers contain MYH7 (type I fibers) Fast fibers contain MYH1 (type IIX fibers), MYH2 (type IIA fibers) ii. Rate of Ca2+ reuptake into SR Sarco (Endoplasmic) Reticulum Calcium ATPase (SERCA) abundance and isoform iii. Rate and economy of ATP transformation Energy substrate and O2 availability Oxidative phosphorylation, glycolysis, phosphocreatine/creatine kinase c. Load i. Muscles are always pitted against some resistance - attached to bones ii. The lighter the load, the faster the contraction Greater loads increase the latency period prior to contraction Greater loads = reduced shortening Greater loads = reduced duration of shortening d. Recruitment i. Many hands make light work, etc. Self-study questions and exercises: Draw a sarcomere and label its constituent parts List and describe each of the myofilaments and myofibrillar proteins that support contraction What is the sliding filament model? What is the sarcoplasmic reticulum and what is its function during contraction? What are T-tubules? What is their function? How would muscle contraction be affected if T-tubules were only located on the surface of myofibers? What is a motor unit? What happens when an action potential reaches a motor neuron’s axon terminals? Which neurotransmitter is required to initiate an end plate potential? Draw the steps involved in cross bridge cycling Which chemical signals are required for myosin binding to actin? Which four properties determine contraction velocity? Which factors influence contractile force? Practice exam questions: 1. Which protein are thick myofilaments comprised of? a) Actin b) Desmin c) Myosin d) Titin 2. Which of the following flows into the myofiber in response to ACh binding to nicotinic receptors on the motor end plate? a) ATP b) Ca2+ c) K+ d) Na+ 3. Which of the following would promote an increase in the force of contraction? a) Activation of only the smaller myofibers b) Stretching myofibers beyond their resting length c) Increasing the number of motor units recruited d) Reducing the frequency of stimulation 1. C; 2. D; 3. C © Dr. Erin Stephenson and MWU 2024 5