Skeletal Muscle Part I Skeletal Muscle Structure and Function PDF

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Skeletal Muscle Part I Skeletal Muscle Structure and Function...

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Skeletal Muscle I: Skeletal Muscle Structure and Function Functions of Skeletal Muscle: ❖ Movement of skeleton ❖ Maintain posture and body position ❖ Maintain body temperature ➢ Skeletal muscle, which represents a relatively large percentage of body mass, is metabolic very active even in a resting state (i.e., generates lots of heat resulting from catabolism of ATP). Skeletal Muscle: ❖ Organ, as it contains several cell/tissue types that all work together to carry out the functions of skeletal muscle ❖ Primary cell type: Muscle fiber or Myofiber ❖ Other cells ➢ Neurons: Function of the skeletal muscle is dependent on the nervous system ■ Must generate the chemical signal to carry out the contractions ➢ Endothelial cells: Part of the blood vessels ■ Element of the cardiovascular system ➢ Fibroblasts: Give rise to connective tissue ■ Prevalent element in skeletal muscle Levels of Organization: ❖ Whole muscle → Muscle fibers/myofibrils→ myofibrils & Myofilaments (represent cytoskeleton - housed in cytoplasm of muscle fiber) → cytoskeletal proteins (e.g. actin and myosin) ➢ Whole muscle is connected to the bone via tendon ■ Primarily composed of myofibers ➢ Myofibril: Long cylindrical like structures ■ Within the myofibril are myofilaments commonly referred to as the thick/ thin filament or actin/myosin filament ● Contain proteins ● Organized as sarcomeres ● Thin filament: Actin/myofilament ● Thick filament: Myosin filament ■ Interactions between the thick and thin filaments result in muscle fiber contractions ■ Housed in the cytoplasm of the muscle fiber therefore they represent the cytoskeleton ● Cytoskeleton is highly organized ➢ Cytoskeletal: proteins act together to form the cytoskeleton ■ Actin and Myosin ❖ Level of organization is critically important in muscle function

❖ Enhancement of muscle function is due to enhancements in the organization of the skeletal muscle ❖ Impairment of muscle function is due to impairments in the organization of the skeletal muscle Application of Concepts: Muscle structure influences function ❖ Enhanced muscle function resulting from exercise is attributable to improvements in muscle structure ❖ Muscle dysfunction resulting from aging, injury, and disease is attributable to structural or chemical abnormalities ❖ Clinical approaches (e.g., rehab and/or medications) to improve muscle function do so by enhancing/restoring muscle structure Muscle Fibers: ❖ Cross-Sectional/Transverse View: Imagine cutting out a muscle from the tendon and cutting the muscle in half ➢ See thin section of the muscle stained with chemicals ➢ Reddish/Pinkish color indicates a muscle fiber ■ Irregular shape ➢ Black dots is the nucleus ■ All except red blood cells have a nucleus ■ See them on the inside and outside ➢ Interstitium is the area between muscle fibers ❖ Longitudinal View: looking along the long axis of the muscle ➢ Tightly packed against each other ❖ Don't need to know ➢ # Fibers / muscle = 100 – 1,000,000 ➢ Muscle Fiber Length = 1 – 600 mm ➢ Myofiber size/cross-sectional area = 100 – 8000 µm2 ➢ (Typical Cell = 10-20 µm) Blood Vessels: ❖ Extensive blood supply over its entire length ❖ Blood high in oxygen content leaves the heart and enters in the arteries, which deliver blood into arteriole and into capillaries ❖ It is within the capillaries where gas exchange occurs ➢ Oxygen diffuses out and carbon dioxide diffuses into the capillaries ➢ Blood low in oxygen content enters back into the heart through the venules, subsequently into the veins and into the heart ❖ Each muscle fiber is surrounded by 3-6 capillaries ➢ Supply oxygen and nutrients and illuminate the waste product Cytoplasm of Muscle Fibers: ❖ Longitudinal View: long axis of the muscle fiber ❖ Cytoplasm contains cytoskeletal elements

➢ Myofibrils: Organized in a parallel organization ■ Linkages between them help in the transmission of contractile tension of force ➢ Mitochondria ➢ Protein: Linkages help keep organization of myofibrils ■ Protein linkages involved in keeping things well organized Organization of Myofilaments within Myofibrils ❖ Myofibers contain structures that are part of the cytoskeleton called myofibrils ➢ In the myofibrils are myofilaments ➢ Black lines perpendicular are called the Z line/Z disk ■ The area between them is the sarcomere (short distance)

➢ Thick filament primarily contains myosin ■ Found in the middle of the sarcomere ● Huge number of sarcomere per myofibril ➢ Thin filament is primarily composed of actin ■ Anchored to the Z disk/Z line ❖ Don't need to know ➢ ~ 5,000 sarcomeres per cm of myofibril length ➢ ~ 100,000 sarcomeres for each myofibril in the biceps brachii ➢ # myofibrils per myofiber in biceps brachii is unknown ➢ ~200-400,000 myofibers within biceps brachii Connective Tissue: Myotendinous Junction: ❖ A tendon is a band of connective tissue (containing primarily collagen) that connects skeletal muscle to bone. Important in the transmission of tension/force to the bone ❖ Tendon enters muscles between muscle fibers Layers of Connective Tissue: ❖ 3 layers ➢ Epimysium ■ Outermost layer of connective tissue that surrounds the whole muscle ➢ Paramecium: Inward; bundles muscle fibers together to form fascicles ■ Could be hundreds/thousands of fibers within a fascicle ➢ Endomysium: Connective tissue that surrounds individual muscle fibers Function of Connective Tissue:

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All layers are involved in distributing/ transmitting contractile tension/force ** Perimysium provides a pathway for blood vessels and nerves to enter muscle Elasticity enables the muscle belly to regain shape when forces are removed Resist stretching of muscle Business end of the muscle fiber resides in the sarcomere as a result of actin/myosin interaction tension/force is going to be produced ➢ This causes the muscle to shorten ➢ The forces are generated within the fiber ➢ Need it transmitted to the endomysium ■ Transfers the force to the paramecium → epimysium → tendon →

change in the joint angle Muscle Fiber/Myofiber Organelles: ❖ Cells that have some of the same organelles as other cells ❖ Nuclei: ➢ Many nuclei (50-1,000/fiber) ■ Events of protein synthesis are initiated in nuclei of myofibrils ■ Myofibers have many nuclei because many proteins have to synthesize and are needed for them to function ● Nucleus houses all the genetic information needed to make the proteins ❖ Muscle Fiber Organelles ➢ Sarcolemma: plasma membrane of a muscle fiber ■ Lipid bilayer ■ Nuclei found near the sarcolemma ➢ Sarcoplasmic Reticulum: endoplasmic reticulum of a muscle fiber ■ Smooth: complex ratus like structure that goes across the entire length of the myofibrils ➢ Transverse Tubule: perpendicular to the sarcolemma ■ Lumen of the transverse tubule: holes on the sarcolemma ➢ Terminal Cisternae: lot of calcium is stored ❖ Mitochondria: 100-1000/fiber ❖ Golgi apparatus ❖ Lysosomes ❖ Satellite cells (not an organelle) ➢ Not found in the cytoplasm rather closely associated with the sarcolemma Location of Satellite Cells: Between endomysium and sarcolemma: ❖ Found around the entire width of the muscle fiber ❖ Important in muscle repair/regeneration after injury Muscle Injury: When does it happen? ❖ Strenuous activities of daily living (e.g., shoveling snow and raking leaves)

❖ Unaccustomed exercise (e.g., 1st workout) ❖ Trauma (e.g., blunt force and surgical) ❖ Resumption of weight bearing activities after prolonged bed rest or limb immobilization (i.e., casting) ❖ Disease (e.g., muscular dystrophy) Changes in Muscle Structure after injury: ❖ 10 minutes after muscle energy: ➢ The muscle fiber Z line are displaced ➢ Structural abnormalities that impair muscle function ■ Loss of contractile strength ❖ 24h Post ➢ No distinguishable sarcomere ➢ Cytoskeleton is so disrupted that the muscle fiber will die ➢ Satellite cells are responsible for creating the replacement muscles Muscle Injury: ❖ Non injured and 10 min post injury: ➢ Non injured: No real notable changes ➢ Normal appearance of muscle fibers is in regular shape ➢ Interstitium still is present and indicative of nuclei ➢ Tight packing of muscle fiber ❖ 3 day post injury: ➢ Intersitum has widened in the space between muscle fibers with lots of nuclei ■ Edema (swelling) is present as interstitium widens and fluid accumulates ■ Some of the “nuclei” (the black dots) are cells of the immune system to “clean up” the mess of tissue debris ● Cells of immune system undergo phagocytosis to clean up the mess ■ Satellite cells undergo cell division ● As a result, daughter cells will interact and fuse together to form baby fibers ➢ Some of the fibers have a pale appearance ❖ 7 day post injury: ➢ Baby fibers/replacement fiber: Small diameter fibers with nucleus in the middle ■ Will grow in size until they are anormal fiber ❖ 21 day post injury: ➢ Full restoration of fiber size and number. Function has returned

FYI: Satellite Cells in Muscle

Repair/Regeneration: ❖ Repair = prevent necrosis of injured myofibers ❖ Regeneration = replacement of necrotic myofibers Application of Concepts: ❖ Restoration of structure and hence, function to injured skeletal muscle is dependent on satellite cells ❖ Effective therapies/treatments for muscle injury must augment satellite cell proliferation and/or other events associated with muscle repair or regeneration ❖ Diminished regenerative capacity of old muscle is attributable to impaired function of satellite cells Cytoskeletal Proteins: ❖ Contractile proteins ➢ Myosin ■ Major protein of the thick filament ■ Several regions of the myosin molecule ■ Tail and globular heads (2-headed structures) ● Globular head protrudes out from center of thick filament ● Binding site on the head/location for the actin protein to bind to ● Myosin ATPase site (enzyme that degrades ATP) ◆ When ATP is broken down, energy is released and the energy drives the events of muscle contraction ● Protruding Arm: At the point at which myosin head connects to the tail region ◆ Head has slight flexibility, similar to making a fist. Your wrist joint and elbow can flex ➢ Your forearm would be the protruding arm ➢ Actin

■ Major protein of the thin filament ■ Each molecule has a binding site for attachment of the myosin head ● Binding of myosin head to actin is critically important in generating the contraction needed to shorten muscle fiber and the joint and cause movement ■ Organize themselves as a long filament/long strand: “string of pearls” ● Twisted on each other ➢ Regulatory proteins ■ Troponin: 3 subunits ● Anchored to tropomyosin and found at regular intervals along the length of the thin filament ■ Tropomyosin: Cord-like structure that wraps around the thin filament ■ Both found on the thin filament (primarily composed of actin) ➢ Structural proteins ■ 100s of proteins ❖ Cross bridge = myosin head + “protruding arm” Orientation of Myosin on Thick Filament: ❖ Myosin is the primary protein of the thick filament ➢ Not the only proteins ❖ Globular head protrudes out the center of the thick filament Troponin Complex: ❖ Anchored to tropomyosin ❖ TnT: Binds tropomyosin ❖ TnC: Binds calcium ➢ Most important part of muscle contraction ❖ TnI: Binds actin ➢ I stands for inhibitory ❖ Troponin complex ~ 7 G actin monomers Types of Muscle Contractions: ❖ Muscle produces tension/force: ➢ Isometric: The length of the muscle doesn’t change ➢ Concentric: The length of the muscle shortens ➢ Eccentric: The length of the muscle increases

Theories of Muscle Shortening (Concentric Contraction): ❖ Fibers are shortening as a result of contractile force ❖ Sliding Filament Theory ➢ Muscle fibers shorten because the (myofilaments) thick filaments slide over the thin filaments ➢ Because these filaments are connected to the Z line, they end up shortening the muscle fiber, aka the whole muscle ■ Area between Z lines is sarcomere ➢ Length of filaments don’t change ➢ A Band: corresponds to the length of the thick filament ■ Contains myosin (thick filament) and regions of the thin filament ■ Main distinguishing characteristics is that it bounds to length of thick filament ■ Only true measure of filament length is the A band, which corresponds to length of myosin and thick filament ➢ H Zone: Fund in the middle of a sarcomere ■ Defines the region that only contains the thick filament ● No overlap between the thick and the thin ➢ I Band: Area between adjacent sarcomeres that contains the Z line and thin filament, but no thick filament ■ No overlap between actin and myosin ➢ Sarcomere shorten → myofibril shorten → Muscle fiber shorten → whole muscle shortens ■ Because the myofilaments are sliding overtop of each other ➢ As a result, certain regions and bands change ■ H Zone and I Band is reduced according to this theory ■ Filaments themselves don’t change ● Only true measure of filament length is A band ■ Main distinguishing characteristic of this theory is that the filament lengths do not change ❖ Cross-bridge Theory ➢ Describes how the actin and myosin filaments are propelled to slide. Includes: ■ Physical interaction between actin and myosin ■ Involvement of both ATP and calcium ● Energy dependent process Cross Bridge Theory: ❖ Proposes how the filaments are intended/propelled to slide as a result of physical interaction between actin and myosin ❖ Cross bridge: Myosin head in protruding arm ❖ Binding: Myosin cross bridge binds to actin molecule

➢ As a result, a power stroke happens ❖ Power Stroke: Due to interaction of actin and myosin, cross bridge bends, pulling thin myofilament inward ➢ ~ 5 nm displacement , ~ 5 pN force ➢ Low displacement and force from one power stroke ■ Does not represent change in joint angle ❖ Detachment: cross bridge detaches at end of power stroke and returns to original conformation ❖ Binding: cross bridge binds to more distal actin molecule; cycle repeated ❖ Your arm is indicative of the myosin molecule: ➢ Upper arm = tail embedded in the thick filament, forearm = protruding arm, fist = myosin head ➢ Once the myosin head binds to actin it cocks (flexing your wrist) ■ As a result a ratcheting action happens (bending elbow) ■ Pulling the Z line towards the center ● Shortening sarcomere length ATP in Cross-Bridge Theory/Cycle ❖ Hydrolysis of ATP provides the energy for cross-bridge cycle (i.e., power stroke)**** ❖ Binding of ATP to myosin dissociates actin from myosin***** ❖ 1) Resting giver: cross bridge is not attached to actin ❖ 2) Cross bridge binds to actin ❖ 3) P1 is released, causing conformational change in myosin ➢ Cocking action ❖ 4) Power stroke causes filaments to slide; ADP is released ➢ Ratcheting action ❖ 5) A new ATP binds to myosin head, allowing it to release form actin ➢ Binding dissociates the myosin head from actin which is needed to perform another power stroke ➢ Stimulus arrives from the nervous system and turn on the ATPase causing it to be broken down ➢ Binding of ATP brakes physical interaction between actin and myosin*** ❖ 6) ATP is hydrolyzed, causing cross bridge to return to its original orientation ➢ Broken down with water ➢ Hydrolysis of ATP provides the energy for the cross bridge cycle Roles of Calcium in Cross-Bridge Cycle: ❖ In a non-contracting myofiber, the binding site for the myosin head on actin is covered by tropomyosin ➢ Tropomyosin: Prevents myosin from binding to actin ❖ Nervous system initiates a rise in intracellular Ca2+ → Ca2+ binds to the TNC subunit of troponin complex → Exposes the myosin binding site on actin because

tropomyosin moves off the binding site ❖ Calcium’s Role: Exposes the binding site to myosin head ❖ Tropomyosin moves off the binding site allowing the myosin head to bind to actin ❖ “Energized” Myosin Head due to ATP already being broken down Amount of Calcium in the Cytoplasm: Critical Determinant of Force Production ❖ # of exposed myosin binding sites on actin → # of myosin heads bound to actin Amount of force generated by: Sarcomere →myofibrils →myofibers →muscle Sliding Filament and Cross Bridge Theories: Relationship to Contractile Force: ❖ Length tension relationship ❖ Whole Muscle or single myofiber ❖ Type of contraction = isometric ❖ Isometric Contraction: When a stimulation is applied, calcium concentrations will rise, ATP will be broken down, etc, power strokes and tension occurs, muscle contraction will be stimulated ➢ The length of the muscle does not change*** (isometric) ➢ Similar to pushing up against a wall or desk ■ Producing contractile tension and force, but length of muscle is unchanged ❖ If you change the length of muscle fiber or whole muscle, the amount of tension will change Relationship between sarcomere length and tension/force: ❖ Degree of overlap between the thick and thin filaments is an important determinant of tension/force production*** ➢ Overlap is needed because myosin needs to bind to actin ➢ No overlap=no binding=little to no force ❖ 100% is normal sarcomere state in a resting state ➢ 120%: The muscle fiber will lengthen ➢ 180%: only way it will lengthen is if the neighboring distance between Z lines increases ➢ 60%: Z lines closer together, very little room for myosin head to do its powerstroke ➢ Very long length cannot produce much tension same as a very short length Length Tension Relationship of Whole Muscle: ❖ Changes in force production attributable: Biomechanical factors Changes in sarcomere length ❖ Ability of muscles to produce force at the joint angels at 90o is the peak of tension being produced ❖ 90o is the strongest degree of ROM ➢ Getting near the end of ROM gets more challenging...