Skeletal Muscle Physiology Lecture Notes

Lecture #9: Skeletal Muscle Physiology Julia Hum, PhD Primary Course Instructor Course Meets: Monday/Wednesday/Friday: 2:00-2:50pm Office Hours: Monday/Wednesday/Friday 11:00am-12:00pm (317B or WebEx)  L9: Learning Object...

Lecture #9: Skeletal Muscle Physiology Julia Hum, PhD Primary Course Instructor Course Meets: Monday/Wednesday/Friday: 2:00-2:50pm Office Hours: Monday/Wednesday/Friday 11:00am-12:00pm (317B or WebEx)  L9: Learning Objectives 1. Reproduce the hierarchical structure of skeletal muscle. 2. Explain the organization and compare and contrast the functions of myosin and actin. 3. Relate the clinical presentation of a disease to the importance of these skeletal elements to the function of the sarcoplasm & sarcomere. 4. Diagram the neuromuscular junction, list the steps of excitation, and characterize the important ions driving action potentials in skeletal muscle. Relate the clinical presentation of a disease to the importance of NMJ function. 5. Define the role of each “key player” in excitation-contraction coupling. 6. Diagram cross-bridge cycling and contraction of the sarcomere. 7. Summarize the principle of preload and relate it to the sarcomere, thin filaments, and thick filaments.  Skeletal Muscle LO1 Guyton and Hall Medical Physiology 13th ed  Skeletal Muscle Structure: Myosin Main body - two heavy chains Head - ATPase activity and contains the actin-interaction site Each head region associates with two light chains: one regulatory light chain and one essential light chain Neck - hinge that allows the head to pivot and pull during contraction LO1,2  Skeletal Muscle Structure: Myosin Tail - anchors the protein within a larger filamentous assembly two heavy chains intertwine to form a coiled coil ~100 assemblies form a bundles Two bundles are joined tail-to-tail to form a thick filament LO1,2  Skeletal Muscle Structure: Actin Troponin Ca++ sensitive protein Uncovers myosin binding site when Ca++ levels rise TnC – Ca++ sensing TnI – inhibit actin/myosin interaction TnT – tethers troponin to tropomyosin Guyton and Hall Medical Physiology 13th ed LO1,2  Relationship of Thick to Thin Filaments Guyton and Hall Medical Physiology 13th ed LO2  The sarcomere is the functional unit of skeletal muscle Sarcomere - is defined between two Z disks Z disk - proteinaceous plates that anchor thin filaments Crossbridge – Region of overlap between the two types of filament Overlap between thick and thin filaments makes a distinct banding patterns LO3  Structural Proteins of the Sarcomere Numerous cytoskeletal proteins constrain the thick and thin filaments to aid in its assembly and maintenance 1. α- Actinin Binds the ends of thin filaments to the Z disks 2. Titin Huge protein, one end is attached to a Z disk, the other to the thick filaments Forms a spring that limits how much the sarcomere can be stretched. It also centers the thick filaments within the sarcomere 3. Dystrophin Large protein associated with Z disks Anchors the contractile array to the cytoskeleton and surface membrane It also aligns the Z disk with disks in adjacent LO3 myofibrils and muscle fibers  Clinical Connection: Muscular Dystrophy Duchenne muscular dystrophy Results from a recessive X-linked mutation in the dystrophin gene Loss of dystrophin function prevents the cytoskeleton and its embedded contractile machinery from attaching to the sarcolemma and the muscle fiber becomes necrotic, causing muscle wasting Patients eventually succumb to respiratory muscle failure LO3  Cross-bridge Cycling LO6  Calcium Regulation of Skeletal Muscle Contraction LO6 Guyton and Hall Medical Physiology 13th ed  Sliding Filaments LO3  Skeletal Muscle Mechanics Preload - stretching a muscle to optimize actin and myosin interaction Sarcomere length is optimal in resting skeletal muscle Stretching a sarcomere can prevent contraction if it physically separates the thick and thin filaments Muscle performance peaks when the potential for crossbridge formation reaches a maximum LO7  Organizational Hierarchy of Skeletal Muscle LO1  Sarcoplasm – cytoplasm of muscle cells Rich in Mg2+, phosphates, and glycogen granules High levels of myoglobin oxygen-binding protein related to hemoglobin Dense with mitochondria tightly alongside the myofibrils to supply the lots of ATP for contraction LO3 ht tps :// miro.med ium.com/m ax/ 786/1*uqG ZL7G XfEbF-RdxLAc-yQ.png  Membrane Systems of the Sarcomere Sarcoplasmic T-Tubule Reticulum Carry action SERCA pumps potentials from Calsequestrin cell surface to structures responsible for Ca++ release Site of specialized Guyton and Hall Medical Physiology 13th ed sensors and ion channels for E-C LO3 coupling  Membrane Systems of the Sarcomere Structure for HOW to contract Where’s the message TO contract? LO3  Neuromuscular Junction (NMJ) LO4  Skeletal Muscle Action Potential LO4  Ion chemical gradients K+ is only major ion that’s high inside the cell relative to outside Chemical gradients drive K+ out of the cell Na+, Cl- and Ca++ are driven into the cell by their chemical gradients LO4  Membrane potential changes LO4  Action potential characteristics Klabunde, Cardiovascular Physiology Concepts, 2e, 2012 LO4  Tissue specific action potentials LO4 Klabunde, Cardiovascular Physiology Concepts, 2e, 2012  Neuromuscular Junction (NMJ) LO4  Clinical Connection: Myasthenia Gravis ht tps :// cached.imagescaler.hb pl.co.uk/res ize/ scaleWid th/ 800/cached.offlinehb pl.hbpl.co.uk/ news/ PGH /G P3-20170926095712312.png Autoimmune condition myasthenia gravis (MG) is the most common disorder affecting neuromuscular transmission Antibodies against nicotinic acetylcholine receptors interfere with normal signaling at NMJ Muscle weakness varies greatly Treatment includes anticholinesterase inhibitors (Stay tuned - next week) LO4 https://www.tha il an dme di cal.n ews/up lo ads/e di to r/fil es/C OVID-19-News(17).jpg FYI - New cases suggest an association of COVID-19 and MG: https://www.acpjournals.org/doi/10.7326/L20-0845  Excitation-Contraction Coupling The spike triggered by ACh release at the NMJ propagates over the sarcolemma Action potentials are electrical events Contraction is mechanical Transduction from electrical to mechanical occurs via “excitation–contraction coupling” Starts when the AP enters the T tubules and LO5 encounters a triad https://s3-us-west-2.am azon aws.c om/co urses-i mag es/wp-co ntent/u pl oad s/sites/1 842 /201 7/05 /262 344 44/fi gu re-38-04-06 f.p ng  Calcium Delivery to Muscle Fibers Depolarization of plasma membrane is transmitted down T-tubules this leads to calcium release from the sarcoplasmic reticulum LO3  Excitation-Contraction Coupling T-tubule L-type Ca++ channels (DHP) Tetrads Mechanics: 1. AP enters T-tubule from sarcolemma 2. DHP receptor opens RyR on SR open 3. Ca++ floods out of SR LO5 Guyton and Hall Medical Physiology 13th ed  Steps in Excitation–Contraction Coupling in Skeletal Muscle LO5  Diagraming the BIG picture together LO4,5,6