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 Ca2+
• Terminal cisternae: part of the SR that lines the T-tubules → when action
potentials arrive, SR is immediately stimulated
to release Ca2+ via receptors in the terminal cisternae
• Longitudinal SR: runs longitudinally along the myofilament

6. • Myofilaments: These 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 Ca2+
• Troponin I (TnI): inhibits actin and myosin binding
• Troponin T (TnT): connects the other troponins to tropomyosin

7. Cytoskeletal proteins
Titin-most abundant, 10% of MP.
 3rd 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

8. 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.

9. 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.
NH2-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.

12. 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

13. 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

14. 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

15. 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): brea
ks down ACh left in the synaptic
cleft to “turn off” the signal

16. 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.

17. 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

18. 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).

19. 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.

20. 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

21. 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
• Ca2+ 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

24. Physiology of Ca2+ 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 Ca2+-release channels closed. When DHP receptors are stimulated by
an action potential, they remove the ryanodine receptors from the Ca2+-release channels, allowing Ca2+ 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 Ca2+ release and
muscle contraction.

27. 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.

28. • 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

30. 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.

32. Mechanism of muscle contraction

33. 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 Ca2+, the troponin–tropomyosin
complex shifts, covering the binding
sites on actin.
• Myosin can no longer bind actin, and
the sarcomere relaxes.

34. Sarcomere Relaxed

35. Sarcomere Partially Contracted

36. Sarcomere Completely Contracted

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

39. 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.
• Components of the DGC include dystrophin, sarcoglycans, dystroglycan, dystrobrevins,
syntrophins, sarcospan, caveolin-3, and NO synthase

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

42. • 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

43. 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).

44. 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 O2
• Occurs once cardiovascular changes have “caught up” with the increase in activity level and
blood flow is now delivering enough O2 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.

48. 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

50. 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.
• Ca2+ ions are pumped back into the SR → without Ca2+, crossbridge formation cannot occur
→ muscle fibers return to their resting state

51. 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

52. 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 Ca2+ 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

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

54. 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.

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

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

58. 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.

59. • 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

60. 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.

61. • 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

63. Oxidative and Glycolative Fibers

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