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Skeletal Muscle Physiology. Muscular System Functions Body movement (Locomotion) Maintenance of posture Respiration –Diaphragm and intercostal contractions.

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Presentation on theme: "Skeletal Muscle Physiology. Muscular System Functions Body movement (Locomotion) Maintenance of posture Respiration –Diaphragm and intercostal contractions."— Presentation transcript:

1 Skeletal Muscle Physiology

2 Muscular System Functions Body movement (Locomotion) Maintenance of posture Respiration –Diaphragm and intercostal contractions Communication (Verbal and Facial) Constriction of organs and vessels –Peristalsis of intestinal tract –Vasoconstriction of b.v. and other structures (pupils) Heart beat Production of body heat (Thermogenesis)

3 Properties of Muscle Excitability: capacity of muscle to respond to a stimulus Contractility: ability of a muscle to shorten and generate pulling force Extensibility: muscle can be stretched back to its original length Elasticity: ability of muscle to recoil to original resting length after stretched

4 Types of Muscle Skeletal –Attached to bones –Makes up 40% of body weight –Responsible for locomotion, facial expressions, posture, respiratory movements, other types of body movement –Voluntary in action; controlled by somatic motor neurons Smooth –In the walls of hollow organs, blood vessels, eye, glands, uterus, skin –Some functions: propel urine, mix food in digestive tract, dilating/constricting pupils, regulating blood flow, –In some locations, autorhythmic –Controlled involuntarily by endocrine and autonomic nervous systems Cardiac –Heart: major source of movement of blood –Autorhythmic –Controlled involuntarily by endocrine and autonomic nervous systems

5 Connective Tissue Sheaths Connective Tissue of a Muscle –Epimysium. Dense regular c.t. surrounding entire muscle Separates muscle from surrounding tissues and organs Connected to the deep fascia –Perimysium. Collagen and elastic fibers surrounding a group of muscle fibers called a fascicle Contains b.v and nerves –Endomysium. Loose connective tissue that surrounds individual muscle fibers Also contains b.v., nerves, and satellite cells (embryonic stem cells function in repair of muscle tissue Collagen fibers of all 3 layers come together at each end of muscle to form a tendon or aponeurosis.

6 Nerve and Blood Vessel Supply Motor neurons –stimulate muscle fibers to contract –Neuron axons branch so that each muscle fiber (muscle cell) is innervated –Form a neuromuscular junction (= myoneural junction) Capillary beds surround muscle fibers –Muscles require large amts of energy –Extensive vascular network delivers necessary oxygen and nutrients and carries away metabolic waste produced by muscle fibers

7 Muscle Tissue Types

8 Skeletal Muscle Long cylindrical cells Many nuclei per cell Striated Voluntary Rapid contractions

9 Basic Features of a Skeletal Muscle Muscle attachments –Most skeletal muscles run from one bone to another –One bone will move – other bone remains fixed Origin – less movable attach- ment Insertion – more movable attach- ment

10 Basic Features of a Skeletal Muscle Muscle attachments (continued) –Muscles attach to origins and insertions by connective tissue Fleshy attachments – connective tissue fibers are short Indirect attachments – connective tissue forms a tendon or aponeurosis –Bone markings present where tendons meet bones Tubercles, trochanters, and crests

11 Skeletal Muscle Structure Composed of muscle cells (fibers), connective tissue, blood vessels, nerves Fibers are long, cylindrical, and multinucleated Tend to be smaller diameter in small muscles and larger in large muscles. 1 mm- 4 cm in length Develop from myoblasts; numbers remain constant Striated appearance Nuclei are peripherally located

12 Muscle Attachments

13 Antagonistic Muscles

14 Microanatomy of Skeletal Muscle

15 Muscle Fiber Anatomy Sarcolemma - cell membrane –Surrounds the sarcoplasm (cytoplasm of fiber) Contains many of the same organelles seen in other cells An abundance of the oxygen-binding protein myoglobin –Punctuated by openings called the transverse tubules (T-tubules) Narrow tubes that extend into the sarcoplasm at right angles to the surface Filled with extracellular fluid Myofibrils -cylindrical structures within muscle fiber –Are bundles of protein filaments (=myofilaments) Two types of myofilaments 1.Actin filaments (thin filaments) 2.Myosin filaments (thick filaments) –At each end of the fiber, myofibrils are anchored to the inner surface of the sarcolemma –When myofibril shortens, muscle shortens (contracts)

16 Sarcoplasmic Reticulum (SR) SR is an elaborate, smooth endoplasmic reticulum –runs longitudinally and surrounds each myofibril –Form chambers called terminal cisternae on either side of the T-tubules A single T-tubule and the 2 terminal cisternae form a triad SR stores Ca ++ when muscle not contracting –When stimulated, calcium released into sarcoplasm – SR membrane has Ca ++ pumps that function to pump Ca ++ out of the sarcoplasm back into the SR after contraction

17 Sarcoplasmic Reticulum (SR)

18 Parts of a Muscle

19 Sarcomeres: Z Disk to Z Disk Sarcomere - repeating functional units of a myofibril –About 10,000 sarcomeres per myofibril, end to end –Each is about 2 µm long Differences in size, density, and distribution of thick and thin filaments gives the muscle fiber a banded or striated appearance. –A bands: a dark band; full length of thick (myosin) filament –M line - protein to which myosins attach –H zone - thick but NO thin filaments –I bands: a light band; from Z disks to ends of thick filaments Thin but NO thick filaments Extends from A band of one sarcomere to A band of the next sarcomere –Z disk: filamentous network of protein. Serves as attachment for actin myofilaments –Titin filaments: elastic chains of amino acids; keep thick and thin filaments in proper alignment

20 Structure of Actin and Myosin

21 Myosin (Thick) Myofilament Many elongated myosin molecules shaped like golf clubs. Single filament contains roughly 300 myosin molecules Molecule consists of two heavy myosin molecules wound together to form a rod portion lying parallel to the myosin myofilament and two heads that extend laterally. Myosin heads 1.Can bind to active sites on the actin molecules to form cross-bridges. (Actin binding site) 2.Attached to the rod portion by a hinge region that can bend and straighten during contraction. 3.Have ATPase activity: activity that breaks down adenosine triphosphate (ATP), releasing energy. Part of the energy is used to bend the hinge region of the myosin molecule during contraction

22 Actin (Thin) Myofilaments Thin Filament: composed of 3 major proteins 1.F (fibrous) actin 2.Tropomyosin 3.Troponin Two strands of fibrous (F) actin form a double helix extending the length of the myofilament; attached at either end at sarcomere. –Composed of G actin monomers each of which has a myosin-binding site (see yellow dot) –Actin site can bind myosin during muscle contraction. Tropomyosin: an elongated protein winds along the groove of the F actin double helix. Troponin is composed of three subunits: –Tn-A : binds to actin –Tn-T :binds to tropomyosin, –Tn-C :binds to calcium ions.

23 Now, putting it all together to perform the function of muscle: Contraction

24 Z line

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26

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28 H Band

29 Sarcomere Relaxed

30 Sarcomere Partially Contracted

31 Sarcomere Completely Contracted

32

33

34 Binding Site Tropomyosin Troponin Ca 2+

35 Myosin

36

37 Excitation-Contraction Coupling Muscle contraction Alpha motor neurons release Ach ACh produces large EPSP in muscle fibers (via nicotinic Ach receptors EPSP evokes action potential Action potential (excitation) triggers Ca 2+ release, leads to fiber contraction Relaxation, Ca 2+ levels lowered by organelle reuptake

38 Excitation-Contraction Coupling

39

40 Sliding Filament Model of Contraction Thin filaments slide past the thick ones so that the actin and myosin filaments overlap to a greater degree In the relaxed state, thin and thick filaments overlap only slightly Upon stimulation, myosin heads bind to actin and sliding begins

41 The lever movement drives displacement of the actin filament relative to the myosin head (~5 nm), and by deforming internal elastic structures, produces force (~5 pN). Thick and thin filaments interdigitate and “slide” relative to each other. How striated muscle works: The Sliding Filament Model

42 Neuromuscular Junction

43 Region where the motor neuron stimulates the muscle fiber The neuromuscular junction is formed by : 1. End of motor neuron axon (axon terminal) Terminals have small membranous sacs (synaptic vesicles) that contain the neurotransmitter acetylcholine (ACh) 2. The motor end plate of a muscle A specific part of the sarcolemma that contains ACh receptors Though exceedingly close, axonal ends and muscle fibers are always separated by a space called the synaptic cleft

44 Neuromuscular Junction

45 Motor Unit: The Nerve-Muscle Functional Unit A motor unit is a motor neuron and all the muscle fibers it supplies The number of muscle fibers per motor unit can vary from a few (4-6) to hundreds (1200-1500) Muscles that control fine movements (fingers, eyes) have small motor units Large weight-bearing muscles (thighs, hips) have large motor units

46 Motor Unit: The Nerve-Muscle Functional Unit Muscle fibers from a motor unit are spread throughout the muscle –Not confined to one fascicle T herefore, contraction of a single motor unit causes weak contraction of the entire muscle Stronger and stronger contractions of a muscle require more and more motor units being stimulated (recruited)

47 Motor Unit All the muscle cells controlled by one nerve cell

48

49 Acetylcholine Opens Na + Channel

50

51 Muscle Contraction Summary Nerve impulse reaches myoneural junction Acetylcholine is released from motor neuron Ach binds with receptors in the muscle membrane to allow sodium to enter Sodium influx will generate an action potential in the sarcolemma

52 Muscle Contraction (Cont’d) Action potential travels down T tubule Sarcoplamic reticulum releases calcium Calcium binds with troponin to move the troponin, tropomyosin complex Binding sites in the actin filament are exposed

53 Muscle Contraction (cont’d) Myosin head attach to binding sites and create a power stroke ATP detaches myosin heads and energizes them for another contaction When action potentials cease the muscle stop contracting

54 Contraction Speed

55 Myosin is a hexamer: 2 myosin heavy chains 4 myosin light chains C terminus 2 nm Coiled coil of two  helices Myosin is a Molecular Motor Myosin S1 fragment crystal structure Ruegg et al., (2002) News Physiol Sci 17:213-218. NH 2 -terminal catalytic (motor) domain neck region/lever arm Nucleotide binding site Myosin head: retains all of the motor functions of myosin, i.e. the ability to produce movement and force.

56 Chemomechanical coupling – conversion of chemical energy (ATP about 7 kcal x mole -1 ) into force/movement. ATP is unstable thermodynamically Two most energetically favorable steps: 1. ATP binding to myosin 2. Phosphate release from myosin Rate of cycling determined by M·ATPase activity and external load Adapted from Goldman & Brenner (1987) Ann Rev Physiol 49:629-636.

57 Shortening Velocity Vependent on ATPase Activity Different myosin heavy chains (MHCs) have different ATPase activities. There are at least 7 separate skeletal muscle MHC genes…arranged in series on chromosome 17. Two cardiac MHC genes located in tandem on chromosome 14. The slow  cardiac MHC is the predominant gene expressed in slow fibers of mammals. Goldspink (1999) J Anat 194:323-334.

58 Peak power obtained at intermediate loads and intermediate velocities. Power Output: The Most Physiologically Relevant Marker of Performance Power = work / time = force x distance / time = force x velocity Figure from Berne and Levy, Physiology Mosby—Year Book, Inc., 1993.

59 shortening isometric lengthening (Isotonic: shortening against fixed load, speed dependent on M·ATPase activity and load) Three Potential Actions During Muscle Contraction: Most likely to cause muscle injury Biceps muscle shortens during contraction Biceps muscle lengthens during contraction

60 Motor Unit Ratios Back muscles –1:100 Finger muscles –1:10 Eye muscles –1:1

61 Recall The Motor Unit: motor neuron and the muscle fibers it innervates Spinal cord The smallest amount of muscle that can be activated voluntarily. Gradation of force in skeletal muscle is coordinated largely by the nervous system. Recruitment of motor units is the most important means of controlling muscle tension. To increase force: 1.Recruit more M.U.s 2.Increase freq. (force –frequency) Since all fibers in the motor unit contract simultaneously, pressures for gene expression (e.g. frequency of stimulation, load) are identical in all fibers of a motor unit.

62 Physiological profiles of motor units: all fibers in a motor unit are of the same fiber type Slow motor units contain slow fibers: Myosin with long cycle time and therefore uses ATP at a slow rate. Many mitochondria, so large capacity to replenish ATP. Economical maintenance of force during isometric contractions and efficient performance of repetitive slow isotonic contractions. Fast motor units contain fast fibers: Myosin with rapid cycling rates. For higher power or when isometric force produced by slow motor units is insufficient. Type 2A fibers are fast and adapted for producing sustained power. Type 2X fibers are faster, but non-oxidative and fatigue rapidly. 2X/2D not 2B. Modified from Burke and Tsairis, Ann NY Acad Sci 228:145-159, 1974.

63 Increased use: strength training Early gains in strength appear to be predominantly due to neural factors…optimizing recruitment patterns. Long term gains almost solely the result of hypertrophy i.e. increased size.

64 Rommel et al. (2001) Nature Cell Biology 3, 1009. The PI(3)K/Akt(PKB)/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy/atrophy. Application of IGF-I to C2C12 myotube cultures induced both increased width and phosphor- ylation of downstream targets of Akt (p70S6 kinase, p70S6K; PHAS-1/4E-BP1; GSK3) but did NOT activate the calcineurin pathway. Treatment with rapamycin almost completely prevented increase in width of C2C12 myotubes. Treatment with cyclosporin or FK506 does not prevent myotube growth in vitro or compensatory hypertrophy in vivo Recovery of muscle weight after following reloading is blocked by rapamycin but not cyclosporin.

65 Performance Declines with Aging --despite maintenance of physical activity Performance Declines with Aging --despite maintenance of physical activity Age (years) 10 2030405060 Performance (% of peak) 0 20 40 60 80 100 Shotput/Discus Marathon Basketball (rebounds/game) D.H. Moore (1975) Nature 253:264-265. NBA Register, 1992-1993 Edition

66 Number of motor units declines during aging - extensor digitorum brevis muscle of humans Campbell et al., (1973) J Neurol Neurosurg Psych 36:74-182. AGE-ASSOCIATED ATROPHY DUE TO BOTH… Individual fiber atrophy (which may be at least partially preventable and reversible through exercise). Loss of fibers (which as yet appears irreversible).

67 Motor neuron loss Central nervous system Motor unit remodeling with aging Muscle Fewer motor units More fibers/motor unit AGING

68 Mean Motor Unit Forces: FF motor units get smaller in old age and decrease in number S motor units get bigger with no change in number Decreased rate of force generation and POWER!! FFFIFRS Maximum Isometric Force (mN) 0 25 50 75 100 125 150 175 200 225 Adult Old Motor Unit Classification Kadhiresan et al., (1996) J Physiol 493:543-552.

69 Muscles in old animals are more susceptible to contraction- induced injury than those in young or adult animals. Muscle injury may play a role in the development of atrophy with aging. Muscles in old animals show delayed and impaired recovery following contraction-induced injury. Following severe injury, muscles in old animals display prolonged, possibly irreversible, structural and functional deficits.

70 Disorders of Muscle Tissue Muscle tissues experience few disorders –Heart muscle is the exception –Skeletal muscle – remarkably resistant to infection –Smooth muscle – problems stem from external irritants

71 Disorders of Muscle Tissue Muscular dystrophy – a group of inherited muscle destroying disease –Affected muscles enlarge with fat and connective tissue –Muscles degenerate Types of muscular dystrophy –Duchenne muscular dystrophy –Myotonic dystrophy

72 Disorders of Muscle Tissue Myofascial pain syndrome – pain is caused by tightened bands of muscle fibers Fibromyalgia – a mysterious chronic-pain syndrome –Affects mostly women –Symptoms – fatigue, sleep abnormalities, severe musculoskeletal pain, and headache

73 Proteins localized in the nucleus, cytosol, cytoskeleton, sarcolemma, and ECM. Cohn and Campbell (2000) Muscle Nerve 23:1459-1471. Since the discovery of dystrophin, numerous genetic disease loci have been linked to protein products and to cellular phenotypes, generating models for studying the pathogenesis of the dystrophies. Muscular Dystrophy: A frequently fatal disease of muscle deterioration Muscular dystrophies have in the past been classified based on subjective and sometimes subtle differences in clinical presentation, such as age of onset, involvement of particular muscles, rate of progression of pathology, mode of inheritance.

74 (Some components of the dystrophin glycoprotein complex are relatively recent discoveries, so one cannot assume that all players are yet known.) DGC dystrophin dystroglycan (  and  ) sarcoglycans ( , , ,  ) syntrophins ( ,  1) dystrobrevins ( ,  ) sarcospan laminin-  2 (merosin) Cohn and Campbell (2000) Muscle Nerve 23:1459-1471. Dystrophin function: transmission of force to extracellular matrix

75 Oxidative and Glycolytic Fibers

76 ATP

77 Creatine Molecule capable of storing ATP energy Creatine + ATPCreatine phosphate + ADP

78 Creatine Phosphate Molecule with stored ATP energy Creatine + ATPCreatine phosphate + ADP

79 Muscle Fatigue Lack of oxygen causes ATP deficit Lactic acid builds up from anaerobic respiration

80 Muscle Fatigue

81 Muscle Atrophy Weakening and shrinking of a muscle May be caused –Immobilization –Loss of neural stimulation

82 Muscle Hypertrophy Enlargement of a muscle More capillaries More mitochondria Caused by –Strenuous exercise –Steroid hormones

83 Steroid Hormones Stimulate muscle growth and hypertrophy

84 Muscle Tonus Tightness of a muscle Some fibers always contracted

85 Tetany Sustained contraction of a muscle Result of a rapid succession of nerve impulses

86 Tetanus

87 Refractory Period Brief period of time in which muscle cells will not respond to a stimulus

88 Refractory

89 Skeletal MuscleCardiac Muscle Refractory Periods

90 Isometric Contraction Produces no movement Used in –Standing –Sitting –Posture

91 Isotonic Contraction Produces movement Used in –Walking –Moving any part of the body

92 Muscle Spindle

93 Muscle Spindle Responses

94 Alpha / Gamma Coactivation

95 Golgi Tendon Organs

96 Developmental Aspects: Regeneration Cardiac and skeletal muscle become amitotic, but can lengthen and thicken Myoblast-like satellite cells show very limited regenerative ability Cardiac cells lack satellite cells Smooth muscle has good regenerative ability There is a biological basis for greater strength in men than in women Women’s skeletal muscle makes up 36% of their body mass Men’s skeletal muscle makes up 42% of their body mass

97 Developmental Aspects: Male and Female These differences are due primarily to the male sex hormone testosterone With more muscle mass, men are generally stronger than women Body strength per unit muscle mass, however, is the same in both sexes

98 Developmental Aspects: Age Related With age, connective tissue increases and muscle fibers decrease Muscles become stringier and more sinewy By age 80, 50% of muscle mass is lost (sarcopenia) Decreased density of capillaries in muscle Reduced stamina Increased recovery time Regular exercise reverses sarcopenia


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