Physiology of muscle contraction.pptx

muscle contraction full physiology

1. Physiology of muscle contraction Dr. N.Vinay kumar DM Resident

2. History of muscle Leeuwenhoek –in 1680 first observed muscle striation . Wilheim keuhne -in 1864 purified “ myosin ” from muscle. Leon fredericque -in 1864 identified A Bands and I Bands based on brifringence . and said A Band doesn’t change during contraction but I Band beomes smaller. Before 1954 muscle contraction was believed to be by folding or coiling of myosin by soluble ATPase enzyme Vladimir and militsa - in 1939 said myosin is the ATPase . Albert szent - in 1942 discovered Actin as activator of Myosin. Anderw f Fluxley -in 1960 explained about sliding filament theory .

3. Primary characteristics of muscle tissue Contractibility:  ability to contract/shorten its length. Excitability:  responds to stimulus (including electrical, hormonal, and mechanical). Extensibility:  ability to extend/stretch. Elasticity:  ability to recoil/return to normal shape when tension is released.

4. Skeletal muscle anatomy review Sarcoplasm:   Muscle cell cytoplasm Contains high amounts of myoglobin and glycogen Sarcolemma:   Muscle cell membrane  Contain  transverse tubules   (T-tubules):   Channels in the sarcolemma running from the surface of the muscle cell into the sarcoplasm and around the myofibrils. Allow action potentials to quickly spread to the myofibrils. Sarcoplasmic reticulum (SR):   Specialized ER containing high levels of Ca 2+   Terminal cisternae:  part of the SR that lines the T-tubules → when action potentials arrive, SR is immediately stimulated to release Ca 2+  via receptors  in the terminal cisternae Longitudinal SR:  runs longitudinally along the myofilament

5. Myofilaments : T hese are individual proteins that together cause muscle contraction.  Sarcomeres:  contractile structures formed by overlapping actin and myosin myofilaments Myosin:  Thick, straight filaments arranged in parallel Have a main shaft and a globular head Actin:  Thin filaments made of 2 long-coiling protein strands Connected to each other at the Z line of sarcomeres Located between each myosin filament Regulatory proteins: Regulate binding of actin to myosin  Tropomyosin:  a rope like protein covering the myosin-binding sites on actin Troponin:  Troponin C ( TnC ): contains binding sites for Ca 2+ Troponin I ( TnI ): inhibits actin and myosin binding Troponin T ( TnT ): connects the other troponins to tropomyosin

6. Cytoskeletal proteins Titin -most abundant, 10% of MP. 3 rd filament. Largest polypeptide known (25000 aa). Extend longitudinally in each half sarcomere from M line to Z disk. Portion of titin in A band is inelastic and that in I band is elastic. Binds to the outside shaft of the thick filament and C protein that encircles and stabilizes the thick filament Nebulin –4% of MP Located close and parallel to actin filament Extends along the length of the thin filament from A band to Z disk In Developing muscle-organization of thin filaments In Mature muscle-serves as scaffold for stability of thin filaments, anchors thin filaments to Z disk others C protein-2% , H protein-1%, Myomesin-2%, M protein-1%, skelemin-1%- stabilize the rod portion of myosin molecules . Aplha actinin(2%), Cap z (1%)-integral components of Z disk

7. Structure of actin (thin filament) and myosin (thick filament): Note the globular head on myosin. The yellow dots on the actin represent the myosin-binding sites, which are covered by tropomyosin in a resting state. Troponins contain the Ca-binding sites and, when Ca is present, induce a conformational change in the troponin–tropomyosin complex, exposing the myosin-binding sites on actin. When myosin can bind actin and ATP energy is present, muscle contraction occurs.

8. Myosin is a hexamer: 2 myosin heavy chains 4 myosin light chains C terminus 2 nm Coiled coil of two a 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. Modified from Vander, Sherman, Luciano Human Physiology, McGraw-Hill.

9. sarcomere structure The  myofibrils are organized in a pattern that creates different bands and zones when viewed under microscopy. These bands are created by overlapping actin and myosin strands. Z line  (also called the  Z band  or  Z disc) :   Anchors and separates 1 sarcomere from another A  sarcomere  is defined as the region between 2 Z lines Anisotropic bands (A bands): Dark bands on microscopy Formed by entire length of thick myosin filaments, which includes overlapping actin filaments at the ends Isotropic bands (I bands): Light bands on microscopy Consist of only thin actin filaments I bands are between the A bands and include the Z line. H zone: Lighter zone in the middle of the A Band Consists of only myosin filaments → excludes the ends of the myosin which are overlapping with actin M bands: Fine, dark line in the center of the H zone Myosin-binding proteins attach here

10. Diagram depicting the microscopic structure of two adjacent sarcomeres: a sarcomere is the area between Z-lines. A band: anisotropic band I band: isotropic band

11. Innervation of Skeletal Muscle Fibers Skeletal muscle cell contraction requires stimulation by an action potential from somatic motor neurons. The neuromuscular junction (NMJ) Also called an  end plate is a synapse  (i.e., connection)   between a skeletal muscle cell and motor neuron Each skeletal muscle cell (i.e., muscle fiber) has 1 NMJ around the midpoint of the cell. Synaptic knob:  a swelling  at the end of the motor neuron Motor end plate:  depression in the sarcolemma of the adjacent muscle fiber, in close association with the synaptic knob Synaptic cleft :  the space between the synaptic knob and the motor end plate Schwann cell:  specialized cell that surrounds and protects the NMJ

12. Process of transmitting a neuronal signal to the muscle cell Acetylcholine is released from synaptic  Vesicles in the synaptic knob. Ach crosses the synaptic cleft. Ach binds to and activates receptors on the motor end plate (there are approximately 50 million Ach receptorsper NMJ) Acetylcholinesterase( AChE ):  breaks down  ACh  left in the synaptic cleft to “turn off” the signal

13. Electron micrograph showing a cross-section through the neuromuscular junction: T is the axon terminal, M is the muscle fiber. The arrow shows junctional folds with basal lamina. Postsynaptic densities are visible on the tips between the folds. The scale is 0.3 µm.

14. Receptors in Muscle Muscle spindle Detect dynamic and static changes in muscle length Stretch reflex Stretch on muscle causes reflex contraction Golgi tendon organ (GTO) Monitor tension developed in muscle Prevents damage during excessive force generation Stimulation results in reflex relaxation of muscle

15. Motor units A group of muscle fibers working together that are controlled by a  single  motor neuron Small motor units: Only a few muscle fibers per neuron Allows for fine muscle control Example: eye muscles Large motor units: Up to several hundred muscle fibers innervated by a single neuron Example: large postural muscles Motor units can be divided into groups , Based on contractile speed, motor units are classified as either slow-twitch (S) or fast-twitch (F). 14   The F motor units are further subdivided into fast-twitch fatigue-resistant (FR), fast-twitch fatigue-intermediate ( Fint ), and fast-twitch fatigable (FF).

16. Depiction of a motor unit: A single motor neuron innervates multiple different muscle fibers (i.e., individual muscle cells). The group of muscle fibers innervated by the same motor neuron are called a motor unit. The motor unit. Motor units include a motor neuron and all of the muscle fibers it innervates. Some, like the one shown here, contain a few muscle fibers. Others contain thousands. The size of the motor unit will influence its force-production capability.

17. How an Individual Muscle Fiber Contracts Excitation A nerve signal arrives at the synaptic knob. Voltage-gated Ca  channels  open, stimulating the release  of Ach  into the synaptic cleft . ACh  binds to and activates ligand-gated ion channels  on the motor  end plate of the muscle fiber. Allows Na +  into the muscle cell  Allows K +  out of the cell This flow of ions reverses the polarity of the sarcolemma = depolarization Depolarization triggers nearby voltage-gated Na +  and K +  channels to open, causing depolarization in these areas → creates a wave of depolarization known as an  action potential  (AP) The AP propagates in all directions throughout the sarcolemma , including down the T-tubule

18. Excitation-contraction coupling The AP stimulates voltage-dependent  dihydropyridine (DHP) receptors: Membrane-bound receptors lining the T-tubules Mechanically tethered to  ryanodine receptors , which sit on (and keep closed) the Ca-release channels in the SR under resting conditions Stimulation of the DHP receptors move the ryanodine receptors → opening the Ca-release channels in the SR Ca 2+  ions flood out of the SR into the sarcoplasm → bind to troponins on the thin filaments (actin) The troponin–tropomyosin complex changes shape → shifts to a new position, allowing actin and myosin to bind

19. Physiology of Ca 2+  release from the sarcoplasmic reticulum in response to an action potential: A wave of depolarization (i.e., the action potential) travels down the T-tubules and triggers the voltage-dependent dihydropyridine (DHP) receptors. These DHP receptors are mechanically tethered to ryanodine receptors, which normally keep the Ca 2+ -release channels closed. When DHP receptors are stimulated by an action potential, they remove the ryanodine receptors from the Ca 2+ -release channels, allowing Ca 2+  to spill out of the sarcoplasmic reticulum and into the sarcoplasm, where they can bind to troponin and stimulate muscle contraction. Dantrolene binds to ryanodine receptors, preventing Ca 2+  release and muscle contraction.

20. Crossbridge cycling Crossbridge cycling is the process by which the myosin and actin move along each other, shortening the sarcomere and causing muscle contraction. This process is also known as the  sliding filament theory of muscle contraction. ATP binds the myosin head. Myosin ATPase hydrolyzes the ATP → ADP: Moves the myosin head into a high-energy “cocked” position This movement is known as the  recovery stroke . The cocked myosin head binds an exposed binding site on actin, forming a  crossbridge . Note: Ca must be present and bound to troponin in order for the myosin-binding sites on actin to be uncovered and available. Myosin binds a new ATP, causing it to release from the actin.

21. Power stroke:   Myosin releases the ADP and phosphate. Myosin head expels the energy → returns to the flexed position, pulling the thin filament with it  Since many myosin heads are bound simultaneously, the thin filament remains in its new position rather than “slipping back” to its original position. Power strokes shorten the I band and moves Z lines closer together: → Sarcomeres shorten and move closer together → Muscle fibers shorten → Entire muscle shortens, generating movement

22. Cross-bridge cycling : The myosin-binding site on actin is exposed when Ca2+ binds troponin. ATP binds the myosin head. Myosin ATPase hydrolyzes the ATP to ADP and phosphate, and this moves the myosin head into a cocked position. With ADP and phosphate still bound, and the head in a cocked position, myosin is able to bind the active sites on actin, forming a cross bridge. The ADP and phosphate are released, and the stored potential energy is released, generating the power stroke: the myosin head returns to its flexed position, pulling the actin filament with it. ATP binds to the myosin head, causing it to release from the actin, and begin the cycle over again. This process allows the myosin to “walk” along the actin filament, shortening the sarcomere.

23. Mechanism of muscle contraction

24. Relaxation The motor  neuron ceases, sending its chemical signal, Ach , into the synapse  at the NMJ. Ach  in the synaptic cleft  is broken down by  AChE . The sarcolemma  repolarizes. Ryanodine receptors close the Ca-release channels  on the SR, preventing further Ca 2+  efflux. Sarco-/endoplasmic reticulum Ca-ATPase (SERCA):  pumps Ca  back into the SR, removing it from the sarcoplasm. Calsequestrin :  binds Ca 2+  within the SR, which stores/sequesters it until a new signal for muscle contraction arrives . Without Ca 2+ , the troponin–tropomyosin complex shifts, covering the binding sites on actin. Myosin can no longer bind actin, and the sarcomere relaxes.

25. Sarcomere Relaxed

26. Sarcomere Partially Contracted

27. Sarcomere Completely Contracted

28. myosin movement occurs due to movement of the light-chain domain (lever arm) when actin catalyzes the release of hydrolysis products from myosin

29. DYSTROPHIN GLYCOPROTEIN COMPLEX It is a multiprotein complex. Functions as a structural link between sarcolemma, cytoskeleton and extra cellular matrix. It aids in blood flow regulation and muscle fatigue recovery. Decrease in function cause fibers to become weak and degeneration. It regulates – recruitment of Nnos , signaling molecule important for relaxation, catalyzes the production of NO. When muscle relaxation occurs, NO diffuses through the muscle cells causing muscle to relax. The DGC is composed of transmembrane, cytoplasmic, and extracellular proteins. C omponents of the DGC include dystrophin, sarcoglycans , dystroglycan , dystrobrevins , syntrophins , sarcospan , caveolin-3, and NO synthase

30. Functions of dystrophin Provides structural integrity link between sarcolemma and cytoskeleton. Acts as molecular shoch absorber during contraction and relaxation. Aids in signaling pathway.

31. Sarcoglycan complex: Possible functions Stabilization of Dystrophin-Glycoprotein Complex Especially Dystrophin– Dystroglycan interaction Regulation of adhesion of Dystrophin-Glycoprotein Complex to Laminin-2 in extracellular matrix ? Role in vascular function associated with blood flow: Especially γ- Sarcoglycan syntorphin functions as modular adaptors that localises signaling molecules such as Nnos ,AQP4 channels ,ion channels etc in association with DGC. Filamin functions Involved in actin reorganization and signal transduction Maintains membrane integrity during force application Structural protein: Z-disc; Myotendinous junction; Intercalated discs

32. Dystrophin associated glycoprotein complex. Dystrophin associated glycoprotein complex and related proteins that help the anchoring of the sarcolemma to the basal lamina. Within brackets under the different proteins are the different diseases that result from deficiency of the respective proteins. (Limb girdle muscle dystrophies (LGDMD); Duchenne muscular dystrophy DMD; Becker muscular dystrophy (BMD); Congenital muscular dystrophy type 1A (MDC1A); Emery– Dreifuss muscular dystrophy (EMD)) (Adapted from Diseases of Muscle and the Neuromuscular Junction Part 1). 

33. Energy sources Adenosine triphosphate concentration in the muscle fiber is only enough to sustain full contraction for 1 to 2 seconds. Therefore, ADP must be rephosphorylated to generate new ATP, allowing the muscle to continue contracting, which requires energy. For immediate energy: Phosphagen system: Creatine phosphate:  an energy-storage molecule that can donate a phosphate group to ADP CP:  transfers the phosphate group from creatine phosphate to ADP → ATP The phosphagen system provides nearly all the energy used in short bursts of intense activity. Myokinase :  can transfer a phosphate group from 1 ADP to another, creating an ATP For short-term energy: anaerobic fermentation Takes over as the phosphagen system is exhausted Glycolysis:  converts glycogen → lactic acid, generating ATP in the process Produces enough ATP to sustain activity for about 30–40 seconds Lactic acid (toxic) builds up → major factor in muscle fatigue For long-term energy: aerobic respiration The major source of energy for activity lasting longer than approximately 30‒40 seconds Requires O 2   Occurs once cardiovascular changes have “caught up” with the increase in activity level and blood flow is now delivering enough O 2  for aerobic respiration to occur Fatty acids and glucose are used to generate ATP through the  Krebs cycle  and  oxidative phosphorylation  (i.e., the electron transport chain (ETC)) Aerobic respiration continues until endurance is depleted via: ↓ Glycogen and blood glucose (BG) Loss of fluid and electrolytes through sweating These energy sources are not used one at a time. Mechanisms blend as exercise continues.

34. Generating Force During Muscle Contractions The length–tension relationship The resting length of the sarcomere has a direct influence on the force generated when the sarcomere  shortens. This is called the  length–tension relationship .  Active tension:  the tension produced by power strokes The amount of tension that can be actively produced is dependent on the starting length of the sarcomere. Overcontracted at rest  (i.e., shorter starting length): The ends of the thick filaments are close to Z lines. Minimal room for them to contract further→ A weak contraction before the fiber runs out of room to contract Overstretched at rest  (i.e., longer starting length): Minimal overlap between actin and myosin Fewer myosin heads can come in contact with the actin.→ Weaker initial contraction  Optimal resting length: The length at which a muscle can produce the greatest force when it contracts Controlled by the CNS Muscle tone:  state of partial contraction that is maintained by the CNS under resting conditions, generating the optimal resting length Passive tension:  tension that resists the myofilaments  being pulled apart  Total muscle tension:  equals active tension plus passive tension

35. Threshold, latent periods, and twitch Threshold:  minimum voltage necessary to generate an AP (an all-or-none response) Latent period: The time between onset of the AP and onset of the muscle contraction (i.e., the twitch) During this time, excitation–contraction coupling is occurring: The AP is being propagated through the sarcolemma. DHP receptors are activated. Ca ions are released from the SR. No increase in tension during the latent period Typically lasts approximately 2 milliseconds Twitch:  An isolated, rapid contraction followed by rapid relaxation  Typically lasts approximately 5‒100 milliseconds  Contraction phase: Occurs during crossbridge cycling Tension increases throughout this phase until peak tension is reached. Relaxation phase , Contraction ends and tension decreases. Ca 2+  ions are pumped back into the SR → without Ca 2+ , crossbridge formation cannot occur → muscle fibers return to their resting state

36. Muscle Twitch Muscle contraction in response to a stimulus that causes action potential in one or more muscle fibers Phases Lag or latent Contraction Relaxation

37. Coordinating twitches so that muscles can do meaningful work A single isolated twitch of a single muscle fiber cannot do meaningful work, and increasing the voltage of the stimulus does not increase the strength of a twitch. Ways to increase the strength of a muscle contraction include: Recruitment  (also called  multiple motor unit summation ): increasing the voltage stimulus to the motor neuron itself excites more nerve fibers → excites more motor units ↑ Frequency of stimulation: Repetitive stimulation → increases tension with each twitch because: The SR cannot fully recover all of the Ca 2+  between twitches Twitches produce heat→ heat causes myosin ATPase to work more efficiently If twitches cannot fully recover before the next twitch starts, tension increases (known as  temporal summation  or  wave summation ) At > 40 stimuli per second:  Muscle has no time to relax at all. Muscle goes into a sustained prolonged contraction known as  tetanus . Tetanus does  not  occur in the body under normal physiologic conditions. Motor units function asynchronously: When 1 motor unit relaxes, another takes over. Allows for “smooth” muscle contractions in which the muscle as a whole does not lose tesion

38. Multiple Motor Unit Summation A whole muscle contracts with a small or large force depending on number of motor units stimulated to contract

39. Multiple-Wave Summation As frequency of action potentials increase, frequency of contraction increases Action potentials come close enough together so that the muscle does not have time to completely relax between contractions.

40. Incomplete tetanus Muscle fibers partially relax between contraction There is time for Ca 2+ to be recycled through the SR between action potentials

41. Treppe Graded response Occurs in muscle rested for prolonged period Each subsequent contraction is stronger than previous until all equal after few stimuli

42. Types of skeletal muscle contraction There are multiple types of muscle contraction based on how the muscle fiber changes length during the contraction: Isometric:  A muscular contraction in which the length of the muscle does not change Auxotonic contraction :  Simultaneous changes in both muscle tension and length I.e., a combination of isometric and isotonic contractions Most regular movements are auxotonic.

43. Isotonic: Maintain constant tension in the muscle as the muscle changes length  Example: bicep curls Have concentric and eccentric phases Concentric:   Shortening of the sarcomere, muscle fiber, and muscle, generating limb movement  E.g., lifting a weight during a bicep curl Eccentric:  Lengthening the muscle while still contracting (i.e., generating force) Occurs when the resistance against the muscle is greater than the force generated  E.g., lowering a bicep curl Concentric vs. eccentric contractions

44. Classification of muscle fibers Currently, muscle fibers are typed using 3 different methods: histochemical staining for myosin ATPase, myosin heavy chain isoform identification, and biochemical identification of metabolic enzymes.

45. There are 3 primary types of skeletal muscle fibers, found in different muscles throughout the body based on their function. Type I fibers: slow-twitch muscle fibers Slow oxidative fibers Fatigue-resistant motor units Examples of activities that require the use of slow oxidative fibers: Back muscles used to maintain posture Running a marathon Type II fibers: fast-twitch muscle fibers Type IIA: Fast oxidative glycolytic fibers Fatigue resistant Used in movement that requires higher sustained power Example of activity using fast oxidative glycolytic fibers: 800-meter race Type IIB: Fast glycolytic fibers Store large amounts of glycogen Fatigue-prone due to buildup of lactic acid during use Examples of activities using fast glycolytic fibers:  Shot put Long jump 100-meter dash Types of skeletal muscle fibers

46. Oxidative and Glycolative Fibers

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