1. WINDSOR UNIVERSITYSCHOOL OF MEDICINE Skeletal Muscle Physiology Dr.Vishal Surender.MD.

2. Learning Objectives -Understand the functional, histological, and anatomic bases for classifying muscle into its three major categories. -Relate the above features to functional differences in the activation and contraction of skeletal and smooth muscle. -Follow the temporal and anatomic steps between the arrival of a nerve impulse at the motor axon terminal and the physical contraction of a skeletal muscle. Relate the functional characteristics for each step to the structures involved in that step. -For each of the critical steps in the above sequence, describe how blockade or failure of the step would lead to failure or compromise of neuromuscular transmission. Be able to determine, from the physiological characteristics of the altered behavior, the nature of the blocking agent. -Understand the characteristics of the control of skeletal muscle contraction by calcium in terms of its switch-like mode of action, explaining why the transition from full on to full off is so rapid. -Explain the relationship between a twitch and a tetanus in skeletal muscle in terms of the known mechanisms of activation and neural control. -Describe (and give examples of) the antagonistic anatomic relationships of skeletal muscle. -Tell how the skeletal lever systems modify the mechanical activity of skeletal muscle. -List, in proper order, the steps in the skeletal muscle crossbridge cycle. Arrange the list in cyclic form, identifying the structures/metabolites involved and the consequences of halting the cycle at each step.

3. -Distinguish between isotonic and isometric conditions and contractions. Give examples of each. -Explain, in terms of the ultrastructure of skeletal muscle, why the production of isometric force depends on the muscle length. -Show, using appropriate diagrams, how the length tension curve applies to both isometric and isotonic contractions. -Using the relationships shown in the force velocity curve for skeletal muscle, derive the power output curve and explain why this curve has a region that predicts optimal power output. Explain, in terms of power output, why all paired values of force and velocity are not equivalent. -Name and describe the three pathways by which adenosine triphosphate is supplied to the contractile machinery, and describe the special features of each one. Explain the physiological consequences of impairments in each of the pathways. -Describe the ways in which smooth muscle is included in the structure of visceral organs, and explain how the particular arrangement is specially adapted to the function of the organ. -Diagram the important steps in the regulation of smooth muscle contraction by calcium ions and myosin phosphorylation, and contrast these with the regulatory process in skeletal muscle. -Explain the special mechanical properties that allow smooth muscle organs to accommodate varying volumes of contents without a large internal pressure.

5. Skeletal Muscle Cell/Fiber: Myofiber, Myofibril, Myofilament.

6. Myofibrils are composed of individual contractile proteins called Myofilaments. • There are two types of Myofilaments- • -Thin Filament is mainly composed of Actin. • -Thick filament is chiefly made up of Myosin. Myofibrils are contractile structures of a Muscle Fiber

7. SARCOMERE • Under a light microscope, the arrangement of thick and thin filaments in a myofibril creates a repeating pattern of alternating light and dark bands. • One repeat of the pattern forms a sarcomere. • The sarcomere is the contracting unit of the muscle. • Within each myofibril the sarcomeres are connected together in series. • During a muscle contraction many of the sarcomeres of a myofibril will be contracting together causing the whole myofibril to shorten. • The sarcomeres within the other myofibrils of the same muscle fiber should be doing the same, so you can imagine all the myofibrils connected in parallel within the muscle fiber contracting at the same time will shorten the muscle fiber.

8. EM of a striated muscle Z line I band A band M line

11. Thick filaments (myosin) • Bundle of myosin proteins shaped like double-headed golf clubs • Myosin head is hinged-Cross bridge region. • Myosin heads have two binding sites • Actin binding site forms cross bridge • Nucleotide binding site binds ATP (Myosin ATPase) • Hydrolysis of ATP • provides energy to • generate power stroke

12. Ultrastructure of Muscle Myosin are motor proteins. 250 myosins join to form the thick filaments Figure 12-3e

13. Thin filaments (actin) • Backbone: two strands of polymerizedglobularactin – form a double helix, has myosin head binding site. • There are two important regulatory protein complexes found on the actin double helix. • Tropomyosin is a protein which sits in between the 2 actin chains. The tropomyosin is an important regulator of the interaction of actin with the myosin crossbridge. • 2) Troponin complex (troponin T, troponin C and troponin I). troponinT is important for binding the troponin complex to the tropomyosin, troponinC binds to calcium and troponinI which is bound to actin and holds the troponin-tropomyosin in “place”. • This “place” is in a position that prevents the myosin crossbridge access to the binding site on the actin molecule.

15. Z line M line Figure 9-5c Boron

16. Changes in the appearance of a Sarcomere during the Contraction of a Skeletal Muscle Fiber

17. Cyclic Interactions Between Myosin and Actin Release Biochemical Energy • The process of contraction involves a cyclic interaction between the thick and thin filaments . • The steps that comprise the crossbridge cycle are attachment of thick-filament crossbridges to sites along the thin filaments, production of a mechanical movement, crossbridge detachment from the thin filaments, and subsequent reattachment of the crossbridges at different sites along the thin filaments.

18. These mechanical changes are closely related to the biochemistry of the contractile proteins. In fact, the crossbridge association between actin and myosin actually functions as an enzyme, actomyosinATPase, that catalyzes the breakdown of ATP and releases its stored chemical energy. • Muscle shortening is due to movement of the actin filament over the myosin filament • Reduces the distance between Z-lines

19. CROSS-BRIDGE CYCLE-1. Myosin heads form cross bridges • Myosin head is tightly bound to actin in rigor state • Nothing bound to nucleotide binding site

20. 2. ATP binds to myosin • Myosin changes conformation, • releases actin

21. 3. ATP hydrolysis • The ATPase activity of myosin hydrolisesATP into: • ADP + Pi(inorganic phosphate) • Both ADP and Pi remain bound to myosin

22. 4. Myosin head changes conformation • Myosin head rotates and binds to new actin molecule • Myosin is in high energy configuration

23. 5. Power stroke • Release of Pi(inorganic phosphate)from myosin releases head from high energy state • Head pushes on actin filament and causes sliding

24. 6. Release of ADP • Myosin head is again tightly bound to actin in rigor state • Ready to repeat cycle

25. Myosin filament Tight binding in the rigor state. The crossbridge is at a 45° angle relative to the filaments. ATP binds to its binding site on the myosin. Myosin then dissociates from actin. 45° 1 2 ATP binding site 3 2 4 1 G-actin molecule ADP ATP 3 2 4 1 3 2 1 4 5 At the end of the power stroke, the myosin head releases ADP and resumes the tightly bound rigor state. 6 The ATPase activity of myosin hydrolyzes the ATP. ADP and Pi remain bound to myosin. 3 ADP Contraction- relaxation Pi Pi Sliding filament 3 2 4 1 3 2 4 1 5 Actin filament moves toward M line. 90° Pi 3 2 4 1 Release of Pi initiates the power stroke. The myosin head rotates on its hinge, pushing the actin filament past it. 5 The myosin head swings over and binds weakly to a new actin molecule. The crossbridge is now at 90º relative to the filaments. 4 The Molecular Basis of Contraction Myosin binding sites Figure 12-9

27. Cross Bridge Cycle

28. (b) Initiation of contraction Ca2+ levels increase in cytosol. 1 4 Power stroke Ca2+ binds to troponin. 2 3 Tropomyosin shifts, exposing binding site on G-actin Pi ADP Troponin-Ca2+ complex pulls tropomyosin away from G-actin binding site. 3 TN Myosin binds to actin and completes power stroke. 4 5 2 G-actin moves Actin filament moves. 5 1 Cytosolic Ca2+ Regulatory Role of Tropomyosin and Troponin Figure 12-10b

29. Rigor mortis • Myosin cannot release actin until a new ATP molecule binds • Run out of ATP at death, cross-bridges never release