1. Gihan Gawish.Dr King Saud University Riyadh Saudi Arabia Saudi Arabia Dr. Gihan Gawish Assistant Professor

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3. Muscles  Muscle is contractile tissue of the body and is derived from the mesodermal layer of embryonic germ cells.  Muscle cells contain contractile filaments that move past each other and change the size of the cell.

4. Gihan Gawish.Dr Function of muscle tissue  Animals use muscles to convert the chemical energy of ATP into mechanical work. ATP

5. Gihan Gawish.Dr Classification of Muscles 1. Heart muscle :  also called cardiac muscle cardiac musclecardiac muscle  It makes up the wall of the heart.  Throughout life, it contracts some 70 times per minute pumping about 5 liters of blood each minute.

6. Gihan Gawish.Dr  Smooth muscle Smooth muscle Smooth muscle  It is found in the walls of all the hollow organs of the body (except the heart).  Its contraction reduces the size of these structures. Thus it: 1.regulates the flow of blood in the arteries 2.moves the foods along through your gastrointestinal tract

7. Gihan Gawish.Dr 3. expels urine from urinary bladder 4. sends babies out from the uterus 5. regulates the flow of air through the lungs The contraction of smooth muscle is generally not under voluntary control.

8. Gihan Gawish.Dr  Skeletal muscle  It is the muscle attached to the skeleton. It is also called striated muscle.  The contraction of skeletal muscle is under voluntary control.

9. Gihan Gawish.Dr Skeletal muscle cell structure  Skeletal muscle is made up of thousands of cylindrical muscle fibers often running all the way from origin to insertion.  The fibers are bound together by connective tissue through which run blood vessels and nerves.

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11. 1. Axon 2. Neuromuscular junction 3. Muscle fiber 4. Myofibril Structure of muscle fiber

12. Gihan Gawish.Dr Each muscle fibers contains 1.an array of myofibrils that are stacked lengthwise and run the entire length of the fiber. 2.mitochondria 3.an extensive smooth endoplasmic reticulum (SER) smooth endoplasmic reticulumsmooth endoplasmic reticulum 4.many nuclei. The multiple nuclei arise from the fact that each muscle fiber develops from the fusion of many cells (called myoblasts).

13. Gihan Gawish.Dr Myoblast  A myoblast is a type of stem cell that exists in muscles. stem cell musclesstem cell muscles  Skeletal muscle fibers are made when myoblasts fuse together muscle fibersmuscle fibers  Myoblasts that do not form muscle fibers differentiate into satellite cells differentiatesatellite cells differentiatesatellite cells

14. Gihan Gawish.Dr  known as Growth differentiation factor 8, is a growth factor that limits muscle tissue growth  It regulates the early fixation of the number of fibers in the life  It is a cytokine that is synthesized in muscle cells (and circulates as a hormone later in life).  It suppresses skeletal muscle development. Myostatin

15. Gihan Gawish.Dr Myostatin in adults,  increased strength and muscle mass comes about through an increase in the thickness of the individual fibers  and increase in the amount of connective tissue.

16. Gihan Gawish.Dr  Because a muscle fiber is not a single cell, its parts are often given special names such as :  sarcolemma for plasma membrane  sarcoplasmic reticulum for endoplasmic reticulum  sarcosome for mitochondrion  sarcoplasm for cytoplasm

17. Gihan Gawish.Dr Each myofibril is made up of arrays of parallel filaments: 1.The thick filaments  They have a diameter of about 15 nm.  They are composed of the protein myosin.

18. Gihan Gawish.Dr 1.The thin filaments  They have a diameter of about 5 nm.  They are composed chiefly of the protein actin along with smaller amounts of two other proteins: –troponin and –tropomyosin.

19. Gihan Gawish.Dr The Anatomy of a Sarcomere  The thick filaments produce the dark A band.  The thin filaments extend in each direction from the Z line. Where they do not overlap the thick filaments, they create the light I band.  The H zone is that portion of the A band where the thick and thin filaments do not overlap.  Shortening of the sarcomeres in a myofibril produces the shortening of the myofibril and, in turn, of the muscle fiber of which it is a part

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21. Actin - The Thin Filaments  Filamentous actin or F-Actin polymerizes from globular G-Actin  They are the principal components of the thin filaments in skeletal muscle.

22. Gihan Gawish.Dr  F-Actin is a helix of uniformly oriented monomers.  They have a polar structure and this polarity from one end to the other is crucial for cell motility.

23. Gihan Gawish.Dr Myosins  Myosins are a large family of motor proteins found in eukaryotic tissues.  They are responsible for actin-based motility. actinmotilityactinmotility  Domains  Most myosin molecules are composed of both a head and a tail domain.  The head domain binds the filamentous actin, and uses ATP hydrolysis to generate force and to "walk"

24. Gihan Gawish.Dr Myosin II  Myosin II, responsible for skeletal muscle contraction  Myosin II contains two heavy chains, each about 2000 amino acids in length, which constitute the head and tail domains.  Each of these heavy chains contains the N-terminal head domain, while the C-terminal tails take on a coiled-coil morphology, holding the two heavy chains together

25. Gihan Gawish.Dr Myosin Dissection. Treatment of muscle myosin with proteases forms stable fragments, including heavy meromysin (subfragments S1 and S2) and light meromyosin.

26. Gihan Gawish.Dr Myosin - the Thick Filaments Myosin - the Thick Filaments  Myosin comes in a greater variety than Actin.  The filaments of Myosin in skeletal muscle are much larger than in nonmuscle cells.  The myosin molecule consists of two identical heavy chains and two pairs of light chains.  The alpha-coil tail is responsible for the spontaneous assembly of myosin molecules into thick filaments.

27. Gihan Gawish.Dr  The heads are responsible for moving the thick filaments against adjacent F-actin filaments in the thin filaments in skeletal muscle.  The structure of thick filaments that myosin molecules form in muscles depends on ionic interactions between the tails.

28. Gihan Gawish.Dr Sliding Filament  When Myofibrils contract the thin and thick filaments move past each other.  Each sarcomer unit of the myofibrils shortens proportionally to the muscle contraction.  Upon contraction, it is the light bands which shorten whereas the dark bands do not change in length.  This is explained by the Actin filaments sliding into the dark region of Myosin filaments.

29. Gihan Gawish.Dr  In the overlapping regions cross-bridges extend about 13 nm from the thick Myosin filaments to the thin Actin filaments.  These cross-bridges are mainly composed of the Myosin heads which are attached to the end of two coiled alpha-helices typically 150nm in length.

30. Gihan Gawish.Dr 1.The thin and thick filaments don’t change during muscle contraction 2.The length of sarcomere decrease during contraction. 3.The force of contraction is generated by a process that actively moves by sliding of filaments. Sliding-Filament Model. Muscle contraction depends on the motion of thin filaments (blue) relative to thick filaments (red).

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32. Muscle contraction and cell motility

33. Gihan Gawish.Dr  The energy for muscle contraction comes from ATP hydrolysis.  The contraction of striated muscle is controlled by the concentration of Ca.  Which is regulated by sarcoplasmic reticulum 2+

34. Gihan Gawish.Dr Myosin Motion Along Actin (hydrolyzed ATP) ATP + H O ADP + P + H 2 i +

35. Gihan Gawish.Dr (hydrolyzed ATP)   A myosin head in the ADP form is bound to an actin filament 1. 1.The exchange of ADP for ATP 2. 2.The release of myosin from actin and substantial reorientation of the lever arm of myosin. 3. 3.Hydrolysis of ATP 4. 4.allows the myosin head to rebind at a site displaced along the actin filament 5. 5.The release of Pi accompanying this binding increases the strength of interaction between myosin and actin and resets the orientation of the lever arm.

36. Gihan Gawish.Dr Troponin and tropmyosin mediate calcium ion regulation of muscle contraction

37. Gihan Gawish.Dr  The physiologic regulator of muscle contraction is Ca.  The effect of calcium ion on the interaction of actin and myosin is mediated by tropomyosin and the troponin complex. 2+

38. Gihan Gawish.Dr Tropomyosin  It is a two stranded alpha –helical rod (70kdal).  This highly elongated protein is aligned nearly parallel to the long axes of the thin filament. Troponin is a complex of three polypeptide chains :  TnC (18kdal): binds Ca ions  TnI (24kdal): binds to actin  TnT (37kdal): binds to tropomyosin.

39. Gihan Gawish.Dr  The troponin complex is located in the thin filaments at intervals of 385A a period set by the length of tropomyosin.  A troponin complex bound to a molecule of tropomyosin regulates the activity of about 7 actin monomers.

40. Gihan Gawish.Dr  The interaction of actin and myosin is inhibited by troponin and tropomyosin in the absence of Ca.  Tropomyosin blocks the binding sites on actin unit in an inhibited thin filament.  Nerve excitation triggers the release of Ca by the sarcoplamic reticulum. 2+

41. Gihan Gawish.Dr  The released Ca binds to the TnC component of troponin and causes conformational changes that are transmitted to tropomyosin and then to actin.  Specifically, tropomyosin moves toward the center of the long helical groove of the thin filament.  Consequently, the S1 heads of myosin molecules can then interact with actin units of the thin filament. 2+

42. Gihan Gawish.Dr  Contractile force is generated and ATP is concomitantly hydrolyzed until Ca ions is removed and tropomyosin again blocks access of the S1 heads.  Thus, Ca controls muscle contraction: Ca TnC Tropomyosin actin 2+ S1 heads of Myosin 2+

43. Gihan Gawish.Dr  The flow of Calcium ions is controlled by the sarcoplasmic reticulum

44. Gihan Gawish.Dr  The outer membrane of a muscle fiber becomes depolarized following the arrival of a nerve impulse at the end plate, which is the junction between nerve and muscle.  The depolarization of the outer membrane is transmitted to the interior of the muscle fiber by the transverse tubules (T tubules).  The T tubules are in close proximity to a net work of extremely fine channels called the sarcoplasmic reticulum, which is a reservoir of calcium ion. nd

45. Gihan Gawish.Dr Schematic diagram of sarcoplasmic reticulum

46. Gihan Gawish.Dr  Ca is the intermediary between the nerve impulse and muscle contraction.  In the resting state: Ca is sequestered in the sarcoplamic reticulum by a Ca active- transport system.  The transport of Ca by the sarcoplasmic reticulum is driven by the hydrolysis of ATP. 2+

47. Gihan Gawish.Dr  There is an ATPase in the sarcoplasmic reticulum that is activated by the Ca.  This Ca + ATPase is an integral part of the Ca pump.  This ATP-driven pump lowers the concentrations of Ca in the cytoplasm of resting muscle and increases the Ca level inside the sarcoplasmic reticulum. 2+

48. Gihan Gawish.Dr  Calsequestrin (protein): binds Ca inside the reticulum.  This highly acidic (44kdal) has more than 40 sites for Ca.  Depolarization of the T tubules membranes causes a sudden release of Ca from the sacs of the sarcoplamic reticulum. 2+

49. Gihan Gawish.Dr  The released Ca then stimulates muscle contraction by binding to the TnC components of the troponin complex 2+

50. Gihan Gawish.Dr  Phosphocreatine is a reservoir of P  The amount of ATP in muscle suffices to sustain contractile activity for only a fraction of a second  Vertebrate muscle contains a reservoir of high potential phosphoryl groups in the form of phosphocreatine

51. Gihan Gawish.Dr  Creatine kinase catalyzes the transfer of a phosphoryl groups from phosphocreatine to ADP to form ATP

52. Gihan Gawish.Dr  Some invertebrates use phosphoarginine to store high potential phosphoryl groups in muscle

53. Gihan Gawish.Dr 2ADP ATP + AMP  In active muscle, the supply of phosphocreatine is rapidly depleted and so the level of ATP drops.  The concentration of ADP and Pi rises, as does the level of AMP by the action of adenylate kinase (myokinase)

54. Gihan Gawish.Dr  the reduced energy charge of active muscle stimulates glycolysis, the citric acid cycle, and the oxidative phosphorylation.  The relative contributions of these processes to the generation of ATP depend on the type of muscle.  Red muscle, which derives its color from myoglobin and the cytochromes of the respiratory chain, has a much more aerobic metabolism than does white muscle.

55. Gihan Gawish.Dr The Link between Glycolysis and the Citric Acid Cycle and oxidative phosphorylation glycolysis Citric acid cycle

56. Gihan Gawish.Dr The Cori Cycle   In actively contracting skeletal muscle, the rate of glycolysis far exceeds that of the citric acid cycle, and much of the pyruvate formed is reduced to lactate, some of which flows to the liver, where it is converted into glucose

57. Gihan Gawish.Dr Lactate formed by active muscle is converted into glucose by the liver. This cycle shifts part of the metabolic burden of active muscle to the liver. The Cori Cycle

58. Gihan Gawish.Dr   In addition, a large amount of alanine is formed in active muscle by the transamination of pyruvate. Alanine, like lactate, can be converted into glucose by the liver.   Why does the muscle release alanine? Muscle can absorb and transaminate branched-chain amino acids; however, it cannot form urea.   Consequently, the nitrogen is released into the blood as alanine.

59. Gihan Gawish.Dr   The liver absorbs the alanine, removes the nitrogen for disposal as urea, and processes the pyruvate to glucose or fatty acids.   The metabolic pattern of resting muscle is quite different. In resting muscle, fatty acids are the major fuel, meeting 85% of the energy needs

60. Gihan Gawish.Dr Homework:  Describe; 1.Glycolysis cycle 2.The citric acid cycle 3.The oxidative phosphorylation