MUSCLE PHYSIOLOGY

Dr Onyango k
6/2/2023
OBJECTIVES
 Understand the organization of muscle fibers and fibrils in
skeletal muscle.
 Name the contractile proteins in the skeletal muscle and give

their functions.
 Draw the labeled diagram of sarcomere.

 Draw the picture of sarcotubular system (STS) and give

function of each component of STS.

INTRODUCTION
 Muscles use chemical energy to generate force
 All muscles transduce a chemical or electrical command into

a mechanical response.
 The trigger for muscle contraction is the rise in free cytosolic

Ca++ concentration.
CLASSIFICATION
 On the basis of structure, metabolism, control mechanisms
and contractile properties like rate and duration of
contraction, fatigability and the ability to regulate contractile
strength, muscles can be classified into three types:
 Skeletal muscle

 Smooth muscle

 Cardiac muscle.
STRUCTURE OF SKELETAL MUSCLE
 A typical skeletal muscle contains many muscle bundles or
fascicles.
 Each fascicle consists of large number of muscle fibers

arranged parallel to each other

 Connective tissue layers in the muscle bundles are

epimysium, perimysium and endomysium.

MUSCLE BUNDLE AND MUSCLE FIBER
 The connective tissue layer around the muscle is called
epimysium.
 The layer covering each fascicle is known as perimysium.

 The layer surrounding each muscle fiber is termed as

endomysium.
 The blood vessels and nerves supplying the muscle fibers are
present within the perimysium.
 All the three layers are made up of collagen and elastin that

helps to transmit the force from the muscles to the bones.

 Muscles are usually attached to bones by collagen fibers

known as tendons.
MYOCYTE
 The structural unit of muscle is muscle fiber that is a single
skeletal muscle cell (myocyte).
 The cell membrane of myocyte is known as sarcolemma and

the cytoplasm as sarcoplasm .

 The muscle fibers are long, cylindrical, multinucleated cells,

extending the entire length of the muscle, and attach to

tendons at both ends.
 They are 10–100 µm in diameter and may extend up to 20

cm in length.
 In embryonic fibers, the nuclei are centrally placed; but

following differentiation after birth, they lie beneath the

sarcolemma, hence peripherally placed .
 Important functions of sarcolemma are:
 It transmits the wave of depolarization originating at the

motor end plate over the entire cell surface to initiate

contraction.
 Besides shielding the muscle fiber, the sarcolemma

contributes to the parallel elastic resistance, i.e. the

resistance to stretch offered by all the connective tissue
layers.
 It has no gap junctions or tight junctions, thereby pro- motes

electrical separation between fibers.

 Characteristically, the sarcoplasm is filled with myofibrils that
extend along the axis of the cell and are connected to the
tendons at both ends of the muscle fiber.
 Each myofibril is 1 µm in diameter and consists of cylindrical

bundles of two types of myofilaments that are referred to as

thick and thin filaments.
 The sarcoplasm contains the usual cytoplasmic organelles

including mitochondria (sarcosomes), sarcoplasmic reticulum,

and Golgi apparatus.
DEVELOPMENT OF MYOCYTES
 The muscle fibers are formed during fetal development by
the fusion of a number of undifferentiated, mononucleated
cells, known as myoblasts.
 At the time of birth, the differentiation of skeletal muscle

fibers is complete.
 These differentiated fibers continue to increase in size during

growth from infancy to adulthood, but no new fibers are

formed from myoblasts.
 After birth, following destruction of skeletal muscle due to
any cause, the existing muscle fibers do not divide to replace
the damaged fibers.
 Instead, new fibers are formed by differentiation of satellite

cells that are located in the adjoining myocytes.

Though the satellite cells are capable of forming a large
number of new muscle fibers, that may not be adequate
enough to restore a severely damaged muscle to its full
strength.
 In such situations, hypertrophy (increase in cell size) of the

remaining muscle fibers usually compensates for the loss.

 Recently, it has been demonstrated that a transcription

factor called myogenin stimulates fibroblasts to become

muscle cells.
 Striations: The most striking feature of skeletal muscle is the
presence of striations due to alternate light and dark bands
throughout the length of the fiber as seen through a light
microscope
 The dark band is also called A band because it is anisotropic

to polarized light.
 The light band is known as I band because it is isotropic to

polarized light .
 Each myofibril is made up of units called sarcomere that

contains different muscle proteins

MUSCLE PROTEINS
There are three types of proteins in skeletal muscle:
 Contractile proteins: myosin and actin

 Regulatory proteins: troponin and tropomyosin

 Attachment proteins: titin, nebulin, alpha actinin, desmin,

myomesin, and dystrophin

MYOSIN FILAMENT
MYOSIN STRUCTURE
MYOSIN
 There are thick and thin filaments in muscle.
 The thick filaments are polymers of myosin II (MW 480,000).

 Myosin filament is a bundle of myosin molecules.

 The head of myosin molecules projects from the filaments

that are arranged in a helical manner .

 The filament is composed of following units: Two intertwined
heavy chains, Two regulatory light chains, and Two alkali
(essential) light chains.
 The myosin II has three regions: two globular heads, neck

(hinge region) and a long tail .

 Each head is made up of amino terminal portions of one
heavy chain forming a complex with two light chains, one
regulatory and one alkali.
 The head contains two binding sites, one for actin and one

for ATP .
 The ATP binding site functions as an ATPase (hydrolyzes ATP).

 The carboxy terminals of the heavy chains coil around each

other in an alpha-helical configuration forming a long rod-like

tail.
 The alkali light chain stabilizes the myosin head and the

regulatory light chain regulates its ATPase activity.

 The tail of each myosin molecule lies along the axis of the
thick filament, and the two globular heads extend out to the
sides, forming the cross-bridges.
 Myosin Hinge In the hinge region, the tail joins the globular

head.
 Arrangement of myosin molecules: The myosin molecules
aggregate with a definite directional arrangement, such that
their tail-ends are directed toward the center of the thick
filaments creating a bare region in the middle consisting of
myosin tails only, while the globular heads point away from
both sides of the tail.
The site of the reversal of polarity of myosin molecules is the
M line where slender cross connections preserve the
organization and alignment of the thick filaments in the
sarcomere.
 Besides titin, proteins like myomesin and C-protein

contribute to the bipolar organization and packing of the

thick filaments.
ACTIN
 The thin filaments are made up of actins.
 The actin filament (F-actin) is made up of globular molecules

of G-actin.
 G-actin is a globular protein with a diameter of 4–5 nm and

MW 42,000.
 G-actin molecules (monomers) are joined from front to back
into long chains that wind about each other forming a double
stranded alpha helical filament known as F-actin (or
filamentous actin) that forms the backbone of the thin
filament.
 The cytoskeletal protein nebulin extends along the length of

the F-actin and plays a role in the regulation of the length of

the thin filament.
ACTIN MOLECULE
 Each actin monomer contains binding sites for myosin,
tropomyosin, troponin I, and other actin monomers.
 As the F-actin undergoes a half-turn every seven G-actin

monomers, a groove is formed down the length of the helix

where lies the long, filamentous protein tropomyosin.
 Each thin filament contains 300–400 actin molecules and 40–

60 tropomyosin molecules.
TROPOMYOSIN
 Tropomyosin is a rod-shaped molecule (MW 70,000)
composed of two strands of polypeptides intertwined in an
alpha helical configuration with a length approximately equal
to seven actin monomers.
 It is located in the groove between two chains of actin .

 The tropomyosin molecules are connected to one another

serially that extends over the entire actin filament covering

myosin-binding sites on the actin monomers.
 The function of tropomyosin is to interfere with the binding of

myosin head to actin.

TROPONIN
 Troponin is a complex of three proteins: Troponin T, Troponin
I, and Troponin C .
 Troponin T has molecular weight 30,000. It binds the troponin

complex to tropomyosin.
 Troponin I (MW 22,000) binds the troponin complex to actin.

 It is called I, because it inhibits the binding of actin to myosin

by blocking the myosin binding site on actin.

 Troponin C Troponin C (MW 18,000) binds to calcium.
 Each troponin complex interacts with one tropomyosin
molecule, which in turn interacts with seven actin monomers.
 The troponin complex also interacts directly with the actin

filaments.
 Troponin is known as the regulatory protein in the

contraction of skeletal muscle.

TITIN
 It is a large, elastic, filamentous, cytoskeletal protein, which
extends from the Z line to the M line.
 It provides framework for the thick filaments by connecting

the Z line to the M line.

 It prevents overextension of the thick filaments and

maintains the central location of the A band.

NEBULIN
 This is a large, filamentous protein that extends along the
length of the thin filaments.
 It is believed to play a role in stabilizing the length of the

actin filaments during muscle development.

 Alpha actinin anchors the thin filaments to the Z line.
 Desmin is present in the intermediate filament of
cytoskeleton of myocyte.
 It connects the Z line to the sarcolemma. It also connects

myofibrils to each other.

 Myomesin is present in the region of M disc. It binds the tail

end of myosin filament to the disc.

It is a large rod like protein that anchors the thin filaments to
the membrane spanning protein beta-dystroglycan, which in
turn is connected to the extracellular matrix pro- tein laminin
through alpha-dystroglycan.
 Dystrophin helps in transfer of force from the contractile

system to extracellular regions through the trans- membrane

proteins.
 These proteins are disrupted in the group of genetic diseases
called muscular dystrophy.
 Absence of these proteins or their mutations leads to muscle

degeneration, weakness and even death.

SARCOMERE
 Is the structural and functional unit of myofibril.
 A single myofibril may be composed of hundreds or

thousands of sarcomeres that are joined end-to-end.

 In each myofibril, thick and thin filaments are arranged in a

repeating pattern in the form of sarcomere .

 Sarcomere is defined as the portion of the muscle fibril

between two successive Z lines.

 The average length of a sarcomere is 2 µm.
 The Z line or Z disc is a network of interconnecting proteins.
 It is oriented perpendicular to the axis of the muscle fiber.

 The thin filaments are anchored to the two sides of each Z

line by alpha actinin.

SARCOMERE IN MYOFIBRIL
STRUCTURE OF SARCOMERE
SARCOMERE IN MUSCLE
CONTRACTION/RELAXATION
THIN FILAMENT
 Each thin filament is 1 µm long and 7 nm in diameter.
 It is composed of the contractile proteins actin, tropomyosin,
and troponin in a ratio of 7:1:1.
 From the Z line, the thin filaments project in parallel arrays
toward the center of the sarcomere where they overlap a
portion of the thick filaments.
 Thus, each sarcomere contains two sets of thin filaments,
one at each end.
 The Z disc not only binds the thin filaments of a single
myofibril together, but connections between the Z discs also
anchor each myofibril to its neighbors.
THICK FILAMENT AND A BAND
 The parallel array of thick filaments located in the middle of
each sarcomere produces A band.
 The thick filament is 1.6 µm long and 10 nm in diameter.

 It consists of the protein myosin

I AND H BAND
 I band lies between the ends of A bands of two adjacent
sarcomeres and includes those portions of the thin filaments
that do not overlap the thick filaments.
 The Z line bisects I band.

 During muscle contraction, the length of the sarcomere (the

distance between two Z lines) decreases.

 This results in shortening of I band but, length of A band

remains unchanged .
 Thus, sarcomeric length is decided by the length of I band.
 H band (H zone) is a narrow, light band in the center of A

band.
 This is the portion of A band showing no overlap (represented

by thick filaments only) as can be seen in a relaxed muscle.

 A transverse M line runs through the middle of H band. The M
line contains proteins that bind the parallel array of thick
filaments.
 Besides, the cytoskeletal protein, titin binds the thick

filaments to the Z lines.

 Titin filaments extend from Z line to M line and thus, are

linked to M-line proteins, thick filaments and Z line proteins.

 Therefore, it plays a key role in organizing and maintaining

the regular array of thick filaments in the middle of each

sarcomere.
 Hexagonal and triangular arrangement: A cross section
through the overlap region of A band shows that each thick
filament is surrounded by a hexagonal array of six thin
filaments, and each thin filament is surrounded by a
triangular arrangement of three thick filaments.

 The globular heads of myosin II project from the surface of
the thick filaments toward the thin filaments and bridge the
gap between them.
 These projections are known as cross-bridges .

 During muscle contraction, they attach to the thin filaments

and pull them.

SARCOTUBULAR SYSTEM
 Inside a muscle fiber, fibrils are surrounded by membr- anous
structures known as sarcotubular system.
 The relationship of sarcotubular system with the I and A

bands of sarcomere in a myofibrils

 It consists of sarcoplasmic reticulum and T (transverse)

tubules
 The T-tubules, also called sarcotubules are tubular extensions
of the sarcolemma, about 0.03 µm in diameter.
 They penetrate to the center of the muscle fiber and

surround the individual myofibrils at the junctions of A and I

band.
ARRANGEMENT OF SARCOTUBULAR SYSTEM
The lumen of the T tubule contains extracellular fluid, which
is a continuation of the ECF surrounding the muscle fibers.
 Once initiated, an action potential is rapidly conducted

along the sarcolemma over the surface of the muscle fiber as

well as into the interior of the muscle cell by the way of the T-
tubules so that deep lying myofibrils are fast activated.
SARCOPLASMIC RETICULUM
 The sarcoplasmic reticulum (SR) in skeletal muscle
corresponds to the endoplasmic reticulum found in other
cells.
 It forms an elaborate membranous network having extensive

anastomosis around each myofibril and runs parallel to the

myofilaments.
 The slender tubules, about 0.04 µm in diameter, have an

elongated portion in the middle and dilated region at both

ends known as lateral sacs or terminal cisternae.
 The cisternae lie in close contact with the T-tubules at the A-I
junction.
 The combination of the T-tubule membrane and its two

neighboring cisternae is called a triad, which plays a vital role

in linking membrane action potentials to muscle contraction .
 In cardiac muscle, it forms a diad due to the presence of one

cistern.
The T-tubules are separated from the terminal cisternae by a
narrow space of about 12–14 nm that contains areas of
densities known as feet.
 The junctional feet involve two integral membrane proteins,

one in the T-tubule membrane, and the other in the

membrane of the terminal cistern.
 The T-tubule protein is a modified voltage-sensitive calcium

channel known as the dihydropyridine (DHP) receptor.

 It is so named because it is blocked by the drug

dihydropyridine.
 The DHP receptors are L-type calcium channels and they are
clustered in groups of four called tetrads.
 Primarily the receptor acts as a voltage sensor rather than a

calcium channel.
 The portion of the terminal cisternae membrane that faces

the T-tubules contains proteins known as the ryanodine

receptors.
They are so called because they bind to the plant alkaloid
ryanodine.
 They mainly act as calcium release channels.

 There is also calcium ATPases present on the membrane of

SR that pumps calcium back into the SR.

 Sarcotubular system (STS) plays a vital role in muscle
contraction as it links T-tubular action potentials (excitation)
with calcium release from the SR that activates the
contractile machinery (contraction).
 When calcium is pumped back into the SR, decline in

cytoplasmic calcium level leads to muscle relaxation.

 Thus, STS is crucial in both contraction and relaxation

process by mediating calcium release and calcium uptake.

 Following depolarization at the motor end plate, action
potentials propagate along the sarcolemma and down the T-
tubule membrane.
 Depolarization of the triad region of the T-tubules induces

conformational changes in each of the four DHP receptor

proteins, which leads to a conformational change in the
ryanodine receptor resulting in opening of the ryanodine
receptor channel.
 Calcium is thus released from the terminal cisternae of the

SR into the cytoplasm, activating cross-bridge cycling.

 The entire process, starting from depolarization of the T-
tubule membrane to the initiation of the cross-bridge cycling
is termed excitation-contraction coupling.
 Further, conformational change in DHP receptor allows

calcium entry from the ECF into the cytoplasm through the
DHP receptor channel and this increase in calcium level
inside the cell can as well activate the ryanodine receptors
resulting in calcium release.
 This mechanism is known as calcium-induced calcium release

(CICR).
 However, this pathway has a much lesser role in contraction

of skeletal muscle.
 CICR plays an important role in cardiac muscle contraction.
 Increase in Ca2+ concentration near the sarcoplasmic

reticulum is known as calcium spark

MECHANISM OF CALCIUM UPTAKE
 The membrane of the SR contains a protein called SERCA
(Sarcoplasmic Endoplasmic Reticulum Calcium ATPase).
 This is so named as it is present in all cells in connection with

the endoplasmic reticulum.

 The protein is a Ca2+ ATPase that pumps free calcium ions

from the sarcoplasm to the SR, from where the calcium ions
are moved to their storage sites in the terminal cisternae.
 The pump relocates two molecules of Ca2+ into the SR for
each molecule of ATP hydrolyzed.
 It becomes active as soon as the Ca2+ concentration in

cytoplasm becomes high.

 In the terminal cisternae, a Ca2+ binding protein called

calsequestrin, favors storage of calcium at high

concentration.
 With decrease in cytoplasmic calcium concentration,

contractile activity ceases and relaxation process begins .

FUNCTIONS OF STS
 It transfers action potential from the surface of the muscle
fiber to the interior, closer to the myofibrils.
 It raises cytoplasmic calcium concentration by calcium

release from SR.

 It ensures muscle relaxation by calcium reuptake by SR

 The cisternae of SR act as storage sites for calcium.