2. Muscle Physiology Musculoskeletal System Jim Pierce Bi 145a Lecture 5, 2009-10

3. Muscle, Bone, and Connective Tissue

4. Muscle Physiology Skeletal Muscle Muscle Unit Muscle Compartment Neurovascular innervation Bones and Joints Motor Unit

5. Muscle Physiology Action Potential in the Motor Neuron Neuromuscular Junction Neurotransmitter Release Post Synaptic Depolarization Muscular Action Potential Chemicomechanical Transduction Muscle Force

6. Muscle Physiology Muscle Muscle Fascicle Muscle Fiber Myofibrils

8. Muscle Physiology CytoskeletonSarcomere Thick Filaments (myosin) Thin Filaments (actin) Transverse Elements (intermediate filaments) Longitudinal Elements (titin and nebulin) External Lamina

9. Muscle Fiber

10. Muscle Physiology Neuromuscular Junction Action Potential Plasma Membrane T-tubules Release of Calcium T-tubule tells Sarcoplasmic Reticulum Calcium causes Myofibril Contraction

11. Neuromuscular Junction

12. Muscle Fiber

13. Action Potential

14. Sarcomere Function

15. Sarcoplasmic Calcium Release T-tubule depolarization causes mechanical opening of calcium channels in terminal cisternae of the sarcoplasmic reticulum. This leads to calcium induced calcium release from the SR.

16. Ryanodine Receptor www.utoronto.ca/maclennan/rint2.htm

17. Ryanodine Receptor

18. Calcium Mature sarcoplasmic reticulum occurs in Mature People Fetal and Neonatal sarcoplasmic reticulum holds less calcium Fetuses and Neonates are more dependent on Serum Calcium

19. Sarcomere Function Sliding Fiber Hypothesis Ca ++ causes Thick Fibers to slide over Thin Fibers Fiber Sliding Causes Force How?

20. Sarcomere Function

22. Cross Bridge Regulation Troponin-C, Troponin-I, Tropomyosin Troponin-C binds up to four calcium ions Troponin-C then moves Tropomyosin away from the Myosin-binding sites on actin.

23. Sarcomere Function

24. Cross Bridge Cycle 1) Myosin with ADP partial P binds Actin Optimal Angle is 90 Degrees 2) Actin-Myosin releases ADP and P Optimal Angle is 45 Degrees 3) Actin-Myosin binds ATP 4) Myosin-ATP releases Actin 5) Myosin partially hydrolyzes ATP

25. Sarcomere

26. Sarcomere

27. Sarcomere Function There is more than one myosin head. The number of myosin heads that can produce force is proportional to the length of overlap of thick and thin fibers. Thus, the force from a sarcomere is a function of the length of the sarcomere.

28. Muscle Physiology The length of the muscle is related to the average length of the sarcomeres. Thus, the force a muscle can produce when stimulated to contract is a function of its length.

29. Muscle Physiology Isometric Contraction Contraction at a constant length We get Force = function (Length)

30. Isometric Length Tension Curve

31. Isometric Contraction There is an optimal length L0 Above L0, the overlapping length of thick and thin filaments gets smaller. Under L0, the overlapping length of thin and thin filaments gets larger.

32. Isometric Contraction

33. Building a Muscle Organ Sarcomere and Myocyte Organization

34. Building a Muscle Organ Sarcomere and Myocyte Organization Which is Better?

35. Building a Muscle Organ Sarcomere and Myocyte Organization Difficult to keep all sarcomeres identical length L T

36. Building a Muscle Organ Sarcomere and Myocyte Organization Short range of motion / force L T

37. Building a Muscle Organ Sarcomere and Myocyte Organization Long range of consistent force L T

38. Building a Muscle Organ Sarcomere and Myocyte Organization At optimal length, more sarcomeres are optimal length L T

39. Building a Muscle Organ Sarcomere and Myocyte Organization Optimization? L T

40. Building a Muscle Organ Sarcomere and Myocyte Organization Adding myocytes increases force Parallel – Increase force, Same Length Series – Increase force, Increase Length

41. Muscle Contraction We’ve Discussed Active Contraction There is also Passive Tension Elasticity from the Connective Tissue Passive Tension increases as we stretch the muscle unit.

42. Passive Tension Tendon Fascia and Supporting Connective Tissue Muscle Fibers

43. Building a Muscle Organ Passive Tension Curves Dense Regular and Dense Irregular Connective Tissue L T

44. Building a Muscle Organ Passive Tension Curves Dense Regular and Dense Irregular Connective Tissue L T

45. Isometric Tension

46. Building a Muscle Organ What happens when myocytes are in parallel? L T

47. Building a Muscle Organ What happens when myocytes are in parallel? Greater Force at L0 Smaller fraction of F0 at extremes L T

48. Building a Muscle Organ What happens when myocytes are in series? L T

49. Building a Muscle Organ What happens when myocytes are in series? Greater Force at L0 Greater fraction of F0 at extremes L T

50. Building a Muscle Organ What happens when the fascial compartment is short? L T

51. Building a Muscle Organ What happens when the fascial compartment is short? Identical force at L0 Smaller fraction of F0 at extremes L T

52. Building a Muscle Organ What happens when the fascial compartment is long? L T

53. Building a Muscle Organ What happens when the fascial compartment is long? Identical force at L0 Greater fraction of F0 at extremes L T

54. Building a Muscle Organ What happens when the tendon is short? L T

55. Building a Muscle Organ What happens when the tendon is short? Same active tension curve shifted right Passive Tension curve shifted down and right L T

56. Building a Muscle Organ What happens when the tendon is long? L T

57. Building a Muscle Organ What happens when the tendon is long? Same active tension curve shifted left Passive Tension curve shifted up and left L T

58. The Muscle Organ Tendon Fascia and Supporting Connective Tissue Muscle Fibers

59. Isotonic Contraction An isotonic contraction is the output of a muscle at constant load. Thus, we perform isotonic contractions when we lift weights and isometric contractions when we maintain posture.

60. Isotonic Contraction When a muscle has a constant load and is stimulated to contract, it gets shorter. Shortening velocity is a function of the load that the muscle bears. Quickest with no load. Quickly with a light load. Slowly with a heavy load. Negatively (they stretch out despite contraction) with a really heavy load.

61. Isotonic Contraction Isotonic contraction is also a function of the initial length of the muscle. If we arbitrarily measure initial shortening velocity at initial length of L0 (the length of muscle with maximal force generation), we can generate a curve: Initial Velocity = Function ( Load )

62. Isotonic Contraction

63. Above maximal loading, muscles can continue to resist the load. There is a point where a massive load can cause rapid lengthening. Why?

64. Isotonic Myosin Cycling

65. Isotonic Contraction Where are the areas which cycle more slowly? Where are the areas that fail more easily? L T

66. Isotonic Contraction Where are the areas which cycle more slowly? Where are the areas that fail more easily? L T

67. Isotonic Contraction How do we accelerate cycling velocity at extremes? And prevent failure? Greater Muscle Length relative to Fascia Length L T

68. Isotonic Contraction How do we improve muscle efficiency? Shorter Muscle Length relative to Fascia Length L T

69. Isotonic versus Isometric No single muscle functions strictly as Isotonic or Isometric Different forces through ranges Muscle “construction” set allows for balance in each muscle

70. Exitation - Contraction Coupling The submaximal response to a single action potential is called a twitch. Repetative action potentials cause summation of twitches, which produces a partial or complete tetanus. Complete tetanus can lead to fatigue.

71. Tetanus

72. Energy Sources Direct Phosphorylation Directly put the P on ADP ADP + ADP --> AMP + ATP Creatine Phosphate --> ATP Catabolic Phosphorylation Glycolysis Oxidative Phosphorylation Mitochondria (NADH / FADH2 from Krebs, glycolysis, catabolism of fatty acids, etc)

73. Energy Sources The alternative to making more ATP is to decrease the concentration of ADP This means adenosine dumping and phosphate dumping.

74. Skeletal Muscle Fiber Types Slow Oxidative (RED) Many Mitochondria Much Myoglobin Fast Glycolytic (WHITE) Large Diameter Large Glycogen Stores Large Calcium pumping ability Fast Oxidative (WHITE) Small Diameter Many Mitochondria Fast Myosin ATPase

75. Energy Sources Remember… Metabolism produces a Carbon Load Electron Load Proton Load Sometimes a nitrogen load

76. Smooth Muscle

77. Multi Unit Smooth Muscle Each cell is independent Each cell is independently innervated Visceral Smooth Muscle The cells share many gap junctions There may be independent pacemaker function There may be intrinsic reflex pathways The cells can also receive innervation for modulation of action potential propagation

78. Smooth Muscle Functions

79. Smooth Muscle Types

80. Smooth Muscle Response

81. Calcium Control How do cytosolic calcium levels control the smooth muscle contraction? There are no troponin and tropomyosin located on the thin filaments. Instead, the myosin isoform in smooth muscle decides when to cycle.

82. Calcium Control Smooth muscle Myosin exists in two forms: Phosphorylated, which can cycle. Naked, which is unable to bind actin (which is unable to cycle) Myosin, surprisingly enough, is phosphorylated by myosin kinase.

83. Calcium Control Myosin Kinase - Calmodulin acts as the “information transducer” to convert cytosolic calcium levels into a myosin phosphorylation state. Thus, cytosolic calcium levels control the rate of myosin cycling.

84. Cross Bridge Cycle

85. Advanced Cross Bridge Cycling

86. P32 Labeled Porcine Carotid At Rest After Potassium Challenge Radioactivity quantitation Bárány and Bárány, 1996a, Biohemistry of Smooth Muscle Contraction, 1996, Academic Press

87. Basic Control via Calcium

88. Control of Cytosolic Calcium

89. Responses to Stimulation

93. Questions?