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MOLECULAR PHYSIOLOGY
Muscular contraction
Tapasya Srivastava and Kunzang Chosdol
Department of Biochemistry
All India Institute of Medical Sciences
Ansari Nagar
New Delhi – 110 029
11-Jan-2007
CONTENTS
Introduction to muscles and its functions
Types of muscles
Skeletal muscle
Smooth muscles
Cardiac muscle
Proteins that make up a skeletal muscle fibre
Mechanism of muscle contractions
Metabolism of the muscle contraction
Disorders of skeletal muscle and smooth muscle
Disease of neuromuscular junction
Keywords
Skeletal muscle; Smooth muscle; Cardiac muscle; Actin; Myosin; Tropomyosin; Troponin; Nebulin; Tinin;
Muscle contraction; Calcium; Sliding filament theory; Neuromuscular junction; Red muscle fibre; White muscle
fibre; Creatine phosphate; ATP utilization; Disorder of muscle
Introduction to muscles and its functions
Muscles make up the bulk of the body and account for about one-third of its weight. Muscle
tissue comprises of units of the muscle cell working in co-ordination with blood vessels,
nerves and connective tissue to form the muscular system. There are around 640 named
muscles in the human body - in addition to thousands of smaller (un-named) muscles.
Approximately 40 to 50 percent of the mass of the human body is composed of muscle
tissue. The muscular system is composed of specialized cells called muscle fibers. Muscle
fibers are contractile cells and their ability to contract not only provides a mechanism for
movement of the internal organs and locomotion of the entire organism but also provides the
force that pushes substances, such as blood and food, through the body. All movements of the
body are a function of the muscular system.
The integrated action of joints, bones, and skeletal muscles produces obvious movements
such as walking and running. Skeletal muscles also produce more subtle movements that
result in various facial expressions, eye movements, and respiration. In addition to
movement, muscle contraction also fulfills some other important functions in the body, such
as posture, joint stability, and heat production. Posture, such as sitting and standing, is
maintained as a result of muscle contraction. The skeletal muscles are continually making
fine adjustments that hold the body in stationary positions. The tendons of many muscles
extend over joints and in this way contribute to joint stability. This is particularly evident in
the knee and shoulder joints, where muscle tendons are a major factor in stabilizing the joint.
Heat production, to maintain body temperature, is an important by-product of muscle
metabolism. Nearly 85 percent of the heat produced in the body is the result of muscle
contraction.
Types of muscles found in the body
There are three types of muscle tissue or muscles: skeletal, smooth, and cardiac. Each type
has a different structure and plays a different role in the body.
Skeletal muscle
Function: Skeletal muscles are responsible for voluntary (conscious) movement. Skeletal
muscles are generally attached to bones and are responsible for moving parts of the body,
such as the limbs, trunk, and face. Most skeletal muscles are consciously controlled by the
nervous system. These muscles usually contract voluntarily, meaning that you think about
contracting them and your nervous system tells them to do so. They can do a short, single
contraction (twitch) or a long, sustained contraction (tetanus). The mechanism of movement
of these muscles will be explained in greater detail in this chapter.
Structure and organisation: Skeletal muscle consists of very long tubular cells (also called
muscle fibres). The average length of skeletal muscle cells in humans is about 3 cm (sartorius
muscle extends upto 30 cm and in contrast, stapedius muscle is only about 1 mm). Their
diameters vary from 10 to 100 µm. Skeletal muscle fibres show characteristic cross-striations
and therefore they are also called striated muscle. Skeletal muscle is innervated by the
somatic nervous system. Skeletal muscle makes up the voluntary muscle. Fig. 1 shows the
skeletal muscle of human tongue (H&E stain).
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Fig. 1: Skeletal muscle of human tongue (H&E stain). Skeletal muscle in the tongue is
arranged in bundles, which typically run at right angles to each other. Both
longitudinally and transversely cut skeletal muscle fibres are present. In both section
planes the nuclei are located in the periphery of the muscle fibre and striations are
visible in longitudinally cut fibres
Skeletal muscle fibres contain many peripherally placed nuclei. Up to several hundred rather
small nuclei with 1 or 2 nucleoli are located just beneath the plasma membrane. These long
and slender muscle fibres or cells vary in length from 1mm to 30 to 60 cm. Skeletal muscle
fibers are grouped into dense bundles called fascicles, which make up the muscle. Varying
movements require contraction of variable numbers of muscles fibers in a muscle. Muscle
fibers work by an electrical stimulus initiated by the nervous system and to prevent the
stimulus uncontrollably passing from one muscle fibre to another requires an insulation
between adjoining muscle cells. This insulation is provided by a connective tissue. The
muscle is surrounded by a layer of connective tissue - the epimysium, which is continuous
with the muscle fascia. The epimysium is well vascularized and helps to bring blood vessels
to all the muscle fibers of the muscle. This helps in providing a constant supply of oxygen.
And within the muscle, the bundles of muscle fibers called muscle fascicles are further
bundled up by connective tissue extending from the epimysium, this connective tissue which
extends into the muscle to surround individual fascicles is called perimysium. From the
perimysium, another delicate network of reticular fibres surrounds each individual muscle
fibre known as endomysium (Fig. 2). The connective tissue in a muscle, thus, transduces the
force generated by the muscle fibres to the tendons. The collagen fibers of the endomysium
and perimysium are interwoven and blend into one another. At each end of the muscle, the
collagen fibers of the epimysium, perimysium, and endomysium come together to form a
bundle known as a tendon or a broad sheet called an aponeurosis. Tendons and aponeuroses
usually attach skeletal muscles to bones. Where a tendon attaches to a bone, the tendon fibers
extend into the bone matrix, providing a firm attachment. As a result, any contraction of the
muscle will exert a pull on its tendon and thereby on the attached bone (or bones).
A typical muscle cell responsible for movement
A muscle fiber is a single, multinucleated muscle cell. A muscle may be made up of hundreds
or even thousands of muscle fibers, depending on the muscles size. Although muscle fiber
makes up most of the muscle tissue, a large amount of connective tissue, blood vessels, and
nerves are also present. Connective tissue covers and supports each muscle fiber and
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reinforces the muscle as a whole. The health of muscle depends on a sufficient nerve and
blood supply. Each skeletal muscle has a nerve ending that controls its activity. Active
muscles use a lot of energy and require a continuous supply of oxygen and nutrients, which
are supplied by arteries. Muscles produce large amounts of metabolic waste that must be
removed by veins. Muscle fibers consist of bundles of threadlike structures called myofibrils.
Each myofibril is made up of two types of protein filaments- thick ones and thin ones. The
thick filaments are made up of a protein called myosin. The thin filaments are made of a
protein called actin. Myosin and actin filaments are arranged to form overlapping patterns,
which are responsible for the light and dark bands that can be seen in skeletal (striated
appearance) muscle. Thin actin filaments are anchored at their midpoints to a structure called
the z-line. The region from one z-line to the next is called a sarcomere the functional unit of
muscle contractions.
Epimysium
Perimysium
Muscle fibre
Endomysium
Fig. 2: Cross section of the muscle showing Epimysium, Perimysium, Endomysium and
Muscle fibres
The Muscle fiber
Skeletal muscle is made up of thousands of cylindrical muscle fibers often running all the
way from origin to insertion. The fibers are bound together by connective tissue through
which run blood vessels and nerves. Each muscle fibre contains an array of myofibrils that
are stacked lengthwise and run the entire length of the fiber, mitochondria, an extensive
endoplasmic reticulum and many nuclei. The multiple nuclei arise from the fact that each
muscle fiber develops from the fusion of many cells (called myoblasts). The number of fibers
is probably fixed early in life. This is regulated by myostatin, a cytokine that is synthesized in
muscle cells (and circulates as a hormone later in life). Myostatin suppresses skeletal muscle
development. Cattle and mice with inactivating mutations in their myostatin genes develop
much larger muscles. Some athletes and other remarkably strong people have been found to
carry one mutant myostatin gene. These discoveries have already led to the growth of an
illicit market in drugs supposedly able to suppress myostatin. Anything that lowers the level
of myostatin also leads to an increase in fiber size. In adults, increased strength and muscle
mass comes about through an increase in the thickness of the individual fibers and increase in
the amount of connective tissue. In the mouse, at least, fibers increase in size by attracting
more myoblasts to fuse with them.
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Because a muscle fiber is not a single cell, its parts are often given special names such as
sarcolemma for plasma membrane, sarcoplasmic reticulum for endoplasmic reticulum,
sarcosome for mitochondrion, sarcoplasm for cytoplasm. However, inspite of the
nomenclature there is an essential similarity in structure and function of these structures and
those found in other cells. The nuclei and mitochondria are located just beneath the plasma
membrane and the endoplasmic reticulum extends between the myofibrils.
Depending on the distribution and interconnection of myofilaments a number of "bands" and
"lines" can be distinguished in the sarcomeres. The essential features of the sarcomere which
is the functional unit of a muscle (Fig. 3) are as follows:
Fig. 3: The sarcomere showing thick and thin filaments. The average length of a
sarcomere is about 2.5 µm (contracted ~1.5 µm, stretched ~3 µm)
•
•
•
•
•
Each myofibril is made up of arrays of parallel filaments. The thick filaments produce
the A band and have a diameter of about 15 nm. They are composed of the protein
myosin. The thin filaments form the light I band and have a diameter of about 5 nm.
The striated appearance of the muscle fiber is created by this pattern of alternating
dark A bands and light I bands.
The A bands are bisected by the H zone and at this juncture the thick and thin
filaments do not overlap. The I bands are bisected by the Z line. The entire array of
thick and thin filaments between the Z lines is called a sarcomere.
They are composed chiefly of the protein actin along with smaller amounts of two
other proteins: troponin and tropomyosin. M-line - band of connections between
myosin filaments (mediated by proteins, e.g. myomesin, M-protein).
Shortening of the sarcomeres in a myofibril produces the shortening of the myofibril
and, in turn, of the muscle fiber of which it is a part.
Smooth muscles
Smooth muscles are usually not under voluntary control. These spindle-shaped muscle cells
are of variable size have a single centrally placed nucleus. The chromatin is finely granular
and the nucleus contains 2-5 nucleoli. They are not striated and interlace to form sheets of
smooth muscle tissue. Smooth muscle fibers are surrounded by connective tissue, but the
connective tissue does not unite to form tendons as it does in skeletal muscles. Most smooth
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muscle cells can contract without nervous stimulation. The innervation of smooth muscle is
provided by the autonomic nervous system. Smooth muscle has the ability to stretch and
maintain tension for long periods of time. Because most of its movements are not
consciously controlled, smooth muscle is referred to as involuntary muscle. Smooth muscles
are found in many internal organs, stomach, intestines, and in the walls of blood vessels. The
contractions in smooth muscles move food through our digestive tract, control the way blood
flows through the circulatory system, and increases the size of the pupils of our eyes in bright
light. The largest smooth muscle cells occur in the uterus during pregnancy (12x600 µm).
The smallest are found around small arterioles (1x10 µm).
Structure of smooth muscle
In the cytoplasm, we find longitudinally oriented bundles of the myofilaments actin and
myosin. Actin filaments insert into attachment plaques located on the cytoplasmic surface of
the plasma membrane. From here, they extend into the cytoplasm and interact with myosin
filaments. The myosin filaments interact with a second set of actin filaments, which insert
into intracytoplasmatic dense bodies. From these dense bodies further actin filaments extend
to interact with yet another set of myosin filaments. This sequence is repeated until the last
actin filaments of the bundle again insert into attachment plaques.
In principle, this organisation of bundles of myofilaments, or myofibrils, into repeating units
corresponds to that in other muscle types. The repeating units of different myofibrils are
however not aligned with each other, and myofibrils do not run exactly longitudinally or
parallel to each other through the smooth muscle cells. Striations, which reflect the alignment
of myofibrils in other muscle types, are therefore not visible in smooth muscle.
Smooth endoplasmatic reticulum is found close to the cytoplasmatic surface of the plasma
membrane. Most of the other organelles tend to accumulate in the cytoplasmic regions around
the poles of the nucleus. The plasma membrane, cytoplasm and endoplasmatic reticulum of
muscle cells are often referred to as sarcolemma, sarcoplasm, and sarcoplasmatic reticulum.
During contraction, the tensile force generated by individual muscle cells is conveyed to the
surrounding connective tissue by the sheath of reticular fibres. These fibres are part of a basal
lamina, which surrounds muscle cells of all muscle types. Smooth muscle cells can remain in
a state of contraction for long periods. Contraction is usually slow and may take minutes to
develop.
Origin of smooth muscle
Smooth muscle cells arise from undifferentiated mesenchymal cells. These cells differentiate
first into mitotically active cells, myoblasts, which contain a few myofilaments. Myoblasts
give rise to the cells, which will differentiate into mature smooth muscle cells.
Structural differences between the organization of a smooth muscle (nonstriated) and the
striated skeletal and cardiac muscles
Actin and myosin are present in all three muscle types. In skeletal and cardiac muscle cells,
these proteins are organized in sarcomeres, with thin and thick filaments. The internal
organization of a smooth muscle cell is very different:
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•
•
•
•
•
A smooth muscle fiber has no T tubules, and the sarcoplasmic reticulum forms a loose
network throughout the sarcoplasm. Smooth muscle tissue has no myofibrils or
sarcomeres. As a result, this tissue also has no striations and is called nonstriated
muscle.
Thick filaments are scattered throughout the sarcoplasm of a smooth muscle cell. The
myosin proteins are organized differently than in skeletal or cardiac muscle cells, and
smooth muscle cells have more cross-bridges per thick filament.
The thin filaments in a smooth muscle cell are attached to dense bodies, structures
distributed throughout the sarcoplasm in a network of intermediate filaments
composed of the protein desmin. Some of the dense bodies are firmly attached to the
sarcolemma. The dense bodies and intermediate filaments anchor the thin filaments
such that, when sliding occurs between thin and thick filaments, the cell shortens.
Dense bodies are not arranged in straight lines, so when a contraction occurs, the
muscle cell twists like a corkscrew.
Adjacent smooth muscle cells are bound together at dense bodies, transmitting the
contractile forces from cell to cell throughout the tissue.
Although smooth muscle cells are surrounded by connective tissue, the collagen fibers
never unite to form tendons or aponeuroses as they do in skeletal muscles.
Types of smooth muscle
Two broad types of smooth muscle can be distinguished on the basis of the type of stimulus,
which results in contraction and the specificity with which individual smooth muscle cells
react to the stimulus:
1.
The multiunit type represents functionally independent smooth muscle cells which are
often innervated by a single nerve terminal and which never contract spontaneously
(e.g. smooth muscle in the walls of blood vessels).
2.
The visceral type represents bundles of smooth muscle cells connected by GAP
junctions, which contract spontaneously if stretched beyond a certain limit (e.g.
smooth muscle in the walls of the intestines, Fig. 4).
Fig. 4: Smooth muscle (Jejunum, human) H&E stain. The outer part of the tube
forming the intestines consists of two layers of smooth muscle - one circular layer and
one longitudinal layer. Both longitudinally sectioned smooth muscle cells and
transversely sectioned smooth muscle cells are seen. Occasionally small nerves between
the two muscle layers are found which regulate the contraction of the muscle around the
gastrointestinal tract
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Cardiac muscle
Cardiac muscles are involuntary muscles like the smooth muscle type but are striated muscles
similar to skeletal muscles. These are highly specialized muscle cells and are only found in
the heart. Cardiac muscles contract without direct stimulation by the nervous system. This is
achieved with the help of A bundle of specialized muscle cells in the upper part of the heart
which send electrical signals through cardiac muscle tissue, causing the heart to rhythmically
contract and pump blood through the body. The basic cardiac Muscle Cell is about 10 - 15 µm
wide and contains only ONE centrally placed Nucleus. Cardiac muscle is innervated by the
autonomic nervous system and exhibits cross-striations between adjacent cells forming
branching fibers that allow Nerve Impulses to pass from cell to cell. Cardiac muscle is for
these reasons also called involuntary striated muscle.
Structure of cardiac muscle
The ultrastructure of the contractile apparatus and the mechanism of contraction largely
correspond to that seen in skeletal muscle cells. Although equal in ultrastructure to skeletal
muscle, the cross-striations in cardiac muscle are less distinct, in part because rows of
mitochondria and many lipid and glycogen droplets are found between myofibrils.
In contrast to skeletal muscle cells, cardiac muscle cells often branch at acute angles and are
connected to each other by extensions of the cell membrane called the intercalated discs.
Intercalated discs invariably occur at the ends of cardiac muscle cells in a region
corresponding to the Z-line of the myofibrils (the last Z-line of the myofibril within the cell is
"replaced" by the intercalated disk of the cell membrane). In the longitudinal part of the cell
membrane, between the "steps" typically formed by the intercalated disk, extensive GAP
junctions are found. T-tubules are typically wider than in skeletal muscle, but there is only
one T-tubule set for each sarcomere, which is located close to the Z-line. The associated
sarcoplasmatic reticulum is organised somewhat simpler than in skeletal muscle. It does not
form continuous cisternae but instead an irregular tubular network around the sarcomere with
only small isolated dilations in association with the T-tubules. A brief Comparison of
Skeletal, Cardiac and Smooth Muscle is shown in Table 1.
Proteins which make up a skeletal muscle fibre
Myosin/Actin
As has been described before, the myofibril was a long tube of cytoskeleton. The myofibril
contains the cytoskeletal elements that allow the muscle to contract. For that reason you will
also see the cytoskeletal elements called the contractile apparatus. The sarcomere is the
functional unit of muscle contractions [resent in the myofibril. These specific type of
cytoskeletal elements involved in the contractile apparatus are microfilaments.
Microfilaments are composed entirely of proteins and are flexible. There are two main
microfilaments: actin and myosin. Actin microfilaments are composed of the actin protein,
while myosin microfilaments are composed of myosin proteins. The protein structure allows
them to have a 3-dimensional shape, and they take on a certain appearance and appear as
light and dark bands. When muscle cells contract, the light and dark bands contained in
muscle cells get closer together. This happens because when a muscle contracts and the
myosin filaments and actin filaments interact to shorten the length of a sarcomere. Apart from
these abundant proteins, there are a number of other proteins, which interact with the actin
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and myosin molecule leading to muscle contraction. To understand how these microfilaments
function we need to understand the arrangement of these proteins independently.
Table 1: Comparison of skeletal, cardiac and smooth muscle
Property
Striations?
Relative Speed
of Contraction
Voluntary Control?
Membrane
Refractory Period
Nuclei per Cell
Control of
Contraction
Skeletal
Muscle
Cardiac
Muscle
Smooth
Muscle
Yes
Fast
Yes
Intermediate Slow
Yes
Short
No
Long
Many
Nerves
Single
Single
Beats
Nerves
spontaneously Hormones
but
Stretch
modulated by
nerves
Yes
Yes
Cells Connected by
No
Intercalated Discs or Gap
Junctions?
No
Actin
The individual actin protein is called a "globular" protein ("g-actin") because of its globular
appearance. The actin microfilament is the result of a number of these globular proteins
coming together to form a long chain (Fig. 5). Two of these chains of g-actin twisted up
together, and the filamentous form is then called "f-actin." The actin microfilament,
although a doublet, is actually rather thin for its length and hence the actin microfilament is
also known as the thin filament. This actin microfilament is also associated with other
molecules, called troponin and tropomyosin for active muscle contraction.
Fig. 5: The actin chains: Two microfilaments of g-actin forming the filamentous ‘factin’
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Myosin
Myosin microfilaments, like actin microfilaments, are made up of many individual myosin
protein molecules (Fig. 6). However, the myosin protein is not globular; instead, it has a
head and a tail region. And each complete myosin molecule in muscle is actually composed
of two of these head-and-tail molecules twisted around each other. The myosin filament is
hence composed of doublet myosin molecules arranged together into large bundles. On
comparison to the actin filament the myosin proteins appear to be more bulky and hence the
name, thick filament. A single thick filament typically has over 200 myosin molecules in it.
The thick filament runs along the long axis of the myofibril.
Fig. 6: Myosin molecule showing head and tail part and the myosin filament formed by
doublet myosin molecules arranged together into large bundles
Tropomyosin and Troponin
Two other proteins associate with actin to form the thin filaments. Tropomyosin is composed
of two polypeptides (a- and b-tropomyosin). Together they make up from 5 to 8% of the
myofibrillar protein. These polypeptides aggregate to form long filaments that fit within the
grove formed by the two chains of actin (Fig. 7). Each molecule spans seven actin molecules
and controls the activity of these actin molecules. Troponin is made up of three subunits.
Troponin C contains calcium binding domain. Troponin T interacts with tropomyosin and
Tropinin I can block the actin binding site for myosin. One set of three troponin subunits is
associated with each molecule of tropomyosin and is involved with the activity of the actin
molecules it interacts with.
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Fig. 7: Arrangement of tropomyosin and troponin in relation to the actin filaments
Nebulin
This protein is a relatively new discovery and not well documented in course books (Fig. 8).
Its exact location as well extent of activity during muscular contraction is still being
researched. It is the biggest actin binding protein not just in its size (600-900kDa) but also its
potential binding capacity of 200 actin monomers. Each monomer is bound by a 35 amino
acid residue that may also bind calmodulin, tropomyosin and troponin and the N-terminal
region binds tropomodulin. The interaction of nebulin with actin is Ca2+-calmodulin
sensitive. Nebulin is proposed to form a "molecular ruler" controlling the length of the thin
filament, as a difference in the length of expressed nebulin corresponds to the length of the
sarcomere.
35 amino acids are repeated 7 times
N
C
The 7x35 repeats are repeated 22 times
Fig. 8: Structure of Nebulin. 7 x 35 amino acid repeats form a unit that is repeated
about 22 times. The N-terminal associates with tropomodulin and so the pointed end of
the thin filament, the C-terminus binds components of the Z-disc
Titin
Titin is the largest polypeptide yet discovered (~3.5 MDa) and a major constituent of the
sarcomere in vertebrate striated muscle. It is a multidomain protein, which forms filaments
approximately 1 micrometre in length spanning half a sarcomere. Single molecules span from
the Z- to M-line Titin has a two major functions: the control of assembly of muscle thick
filaments and a role in muscle elasticity by forming a connection between the ends of the
thick filament ans the Z-line as shown in the diagram. Without this there would be force
imbalances in the opposite halves of thick filaments during active contraction).
Alpha- actinin
A family of actin filament crosslinking and bundling protein which are typically calcium
sensitive in non-muscle cells and calcium insensitive in muscle cells. α-actinin is composed
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of two identical anti-parallel peptides, with the actin binding domain close to the N terminus,
followed by 4 spectrin-like repeats and terminating with two EF-hands (calcium binding
motifs) (Fig. 9). Caicium binding inhibits the cross-linking function of α-actinin. In calcium
insensitive isoforms these EF-hands are not active. α-actinin is a homodimer of two 100 kDa
subunits. Under an electron microscope, α-actinins are rod like molecules, 40-5- nm long and
4-5 nm in width.
C terminal
EF/Ca2+ binding domain
N terminal
Actin binding domain
Central part
Overlapping homodimer
Fig. 9: α-actinin is a homodimer of two 100 kDa subunits, rod like molecules with the
actin binding domain close to the N terminus, followed by 4 spectrin-like repeats and
terminating with two EF-hands (calcium binding motifs)
Myomesin
Proteins, myomesin and M-protein are the main constituents of the role of M-band bridges,
which connect the neighboring thick filaments. Both proteins consist of the unique head
domain followed by a conserved sequence of immunoglobulin (Ig) and fibronectin type III
(Fn) domains. Myomesin seems to be the essential M-band component and might works as a
bi-directional spring, providing the elasticity for the M-bridges.
Mechanism of muscle contractions
Organisation of cytoskeletal proteins on the contracting muscle
The spatial relation between the filaments that make up the myofibrils within skeletal muscle
fibres is highly regular. This regular organisation of the myofibrils gives rise to the crossstriation, which characterises skeletal and cardiac muscle. Sets of individual "stria" within a
myofibril correspond to the smallest contractile units of skeletal muscle, the sarcomeres (Fig.
3).
Physiology of the contracting muscle
The sarcomere is the basic unit of contraction . when the muscle receives a signal from the
nerves, the muscles contract. The muscular contraction and relaxation is a result of changes in
the chemicals released at the neuromuscular junction.
Sliding filament theory: This is the accepted theory for the basic mechanism of muscle
contraction. The theory was given by two groups in England: A.F. Huxley and Niedergerke
in 1954, and H.E. Huxley and Hanson also in 1954. They conducted experiments on the
changes in sarcomere length and in I band length during contraction of an electrically
stimulated frog fiber. The length of the sarcomeres, A and I-bands were measured on
densitometer tracings. The fiber was stimulated electrically and then allowed to shorten.
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During the experiment, it was discovered that during contraction the length of the actin
containing thin filaments and the length of the myosin containing thick filaments remained
constant. Thus, during contraction the length of the sarcomere and I-band decrease, the
overlap between thick and thin filaments increases but the length of the thick and thin
filaments remains unchanged (Fig. 10). Consequently, the filaments must slide past each
other. The physiological interpretation of the sliding filament theory was tested by measuring
the tension of a single muscle fiber at different sarcomere length. Maximum tension was
obtained at rest length, between 2.0-2.25 micron, when all crossbridges were in the overlap
region between thick and thin filaments. When the muscle fiber was stretched so that the
sarcomere length increased from 2.25 to 3.675 micron and consequently the number of
crossbridges in the overlap region decreased from maximum to zero; the tension fell from
100% to 0. The crossbridges are uniformly distributed along the thick filaments with the
exception of a short bare zone in the middle. The crossbridges seem to be identical and are
the site of the interaction between thick and thin filaments. The tension is the algebraic sum
of the tension produced at each individual site. At or above rest length the tension is directly
proportional to the number of crossbridges in the overlap region between thick and thin
filaments.
Percent tension
A
100%
B
D
C
50%
Resting
muscle length
70% 100% 130%
Shortened
muscle
170%
Stretched
muscle
Fig. 10: Sliding filament theory
The banding positions (A and I bands) of the thin (actin) and thick (myosin) filaments can be
explained further with the following representations, which have originally been well
documented by electron microscopy by many scientists:
• In the relaxed state (corresponding to Point C on the graph given in Fig. 10): The
muscle is stretched to a point where there is very little overlap between actin and
myosin. The isometric tension will be low (Fig. 11a)
• When muscle contracts the actin, filaments slide into the A band, overlapping with
myosin. At point B on the graph of Fig. 10 there is considerable overlap between actin
and myosin. There are many active crossbridges, so the isometric tension will be high
(Fig. 11b). As a consequence of muscle contraction - the Z lines move closer together,
the I band becomes shorter and the A band stays at the same length
• At point D (Fig. 10) there is a lot of overlap between actin and myosin, but the actin
filaments are pushing on each other. This distorts the filaments, weakening the
crossbridges (Fig. 11c).
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Actin
Myosin
Z line
Z line
Sarcomere
relaxed
Fig. 11a: Muscle filaments in relaxed state
Actin
Myosin
Z line
Sarcomere
contracts
Z line
Fig. 11b: Muscle filament during contraction
Actin and myosin
overlap
Myosin
Z line
Actin
Sarcomere Z line
contracts
to maximum
Fig. 11c: Muscle filament during maximum contraction. The sarcomere is about 30%
Muscle contraction is a little like climbing a rope. The crossbridge cycle is: grab -> pull ->
release, repeated over and over. In the resting state, the actin and myosin (which have a
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natural affinity for each other) are prevented from coming into contact. The presence of Ca++
allows their interaction. So, the trigger for muscle contraction is a sudden inflow of Ca2+.
In the resting state the protein tropomyosin winds around actin and covers the myosin binding
sites. Troponin and tropomyosin, form a complex weave between the actin and myosin, and
prevents their contaction the resting state. The Ca binds to troponin, and this action causes the
tropomyosin to be pulled to the side, exposing the myosin binding sites and allows the
interaction between actin and myosin. The presence of ATP instigates muscular contraction.
In muscle Ca2+ is stored in the sarcoplasmic reticulum (SR) (Fig. 12). The sarcolemma is the
surface membrane of the entire fiber. It will have a single neuromuscular junction somewhere
on its surface and it will not be electrically coupled to any of its neighbouring fibers. The Ttubular membranes are extensions of the sarcolemma. They contain extracellular fluid (high
in Ca and Na ions). They are continuous tubes of sarcolemmal membrane that run through
(transversely) the muscle fiber. In mammals the T-tubules lie at the boundary of the A and I
bands (so there are 2 tubules per sarcomere). So, the t-tubule serves to propagate the
sarcolemmal action potential deep into the fiber, bringing the excitation close to the SR
membrane that surrounds each sarcomere. The sarcoplasmic reticlum (SR) is the Ca store. It
is a diffuse membrane structure that surrounds the sarcomere and approaches closesly to the
t-system where the SR structure chanes and is called terminal cisternae of the SR. Its
membranes contain essentially 2 proteins: the Ca- ATPase (facing sarcomere) and the Carelease channel (close to and facing the t-tubules). The calcium used to activate actin-myosin
interaction is stored in and released from the SR.
Fig. 12: Above figure showing sarcolema with sarcoplasmic reticulum
Calcium release is stimulated by nerves, which contact muscle through a neuromuscular
junction
The nerve releases acetylcholine and generates a muscle action potential. The action potential
travels down the T-tubule and causes the sarcoplasmic reticulum (SR) to release Ca. After the
contraction the Ca must be rapidly pumped back into the SR so the muscle can contract
again.
15
The Neuromuscular Junction
Nerve impulses (action potentials) traveling down the motor neurons of the sensory-somatic
branch of the nervous system cause the skeletal muscle fibers at which they terminate to
contract. The junction between the terminal of a motor neuron and a muscle fiber is called the
neuromuscular junction (Fig. 13a). The neuromuscular junction is also called the myoneural
junction. The terminals of motor axons contain thousands of vesicles filled with acetylcholine
(ACh). When an action potential reaches the axon terminal, hundreds of these vesicles
discharge their ACh onto a specialized area of postsynaptic membrane on the fiber (Fig. 13b).
This area contains a cluster of transmembrane channels that are opened by ACh and let
sodium ions (Na+) diffuse in.
(a)
Nerve impulse passes
down the axon
Calcium channel Ca2+ causes exocytosis
of vesicles for Ach
release
Presynaptic membrane
Fused vesicles release Acetylcholine (Ach)
Choline pump
Choline
recycled
Synaptic cleft
Ach
Ach breakdown
A
cholinesterase
Postsynaptic membrane
Ach receptors
Muscle
(b)
Fig. 13: (a) Neuromuscular junction -The junction between the terminal of a motor
neuron and a muscle fiber; (b) Release of acetylcholine when nerve impulse passes down
the axon and its consequences
When a single nerve enters a muscle it splits and makes neuromuscular junctions (NMJs)
with several muscle cells. When the nerve fires the whole motor unit is stimulated and the
16
muscle cells contract together. Muscles with large motor units have coarse movements.
Muscles with small motor units give fine, graded movements.
Excitation and contraction of skeletal muscle
The area of contact between the end of a motor nerve and a skeletal muscle cell is called the
motor end plate. Small branches of the motor nerve form contacts (boutons) with the muscle
cell in a roughly eliptical area. The excitatory transmitter at the motor end plate is
acetylcholine. The space between the boutons and the muscle fibre is called primary synaptic
cleft. Numerous infoldings of the sarcolemma in the area of the motor end plate form
secondary synaptic clefts. Motor end plates typically concentrate in a narrow zone close to
the middle of the belly of a muscle. The excitable sarcolemma of skeletal muscle cells will
allow the stimulus to spread, from this zone, over the entire muscle cell.
Cellular resting potential
If we remember that myofibers are basically water with some dissolved ions separated from
the extracellular space, which is also mostly water with some dissolved ions, then the
presence of a resting potential may make more sense. In much the same way as a battery
creates an electrical potential difference by having different concentrations of ions at its two
poles, so does a muscle cell generate a potential difference across its cell membrane. The
ATP driven sodium-potassium pump maintains an artificially low concentration of sodium
and high concentration of potassium in the intracellular space, which generates a resting
potential difference on the order of -95 mV (Fig. 14a, b).
Depolarization
Depolarization is achieved by other transmembrane channel proteins. When the potential
difference near these voltage sensitive proteins reaches a threshold level, the protein
undergoes a magical conformational change that makes the membrane permeable to sodium.
Extracellular sodium immediately rushes in, drawn by both the charge difference and
concentration gradient, and locally depolarizes the cell. Almost immediately, potassium also
moves along in concentration gradient out of the cell and the membrane potential is restored.
As an interesting side note, this is the mechanism by which potassium chloride is used to
induce cardiac arrest: by eliminating the potassium concentration gradient, the depolarized
cardiac muscle cells are unable to repolarize for their next beat.
This depolarization is an extremely localized phenomenon, depending on diffusion over a
few milliseconds. Some system is required to carry this signal to the myofibrils deep within
the cell body. The sarcolemma, or cell membrane, invaginates to form a network of
transverse (or T-) tubules that span the cross section of each fiber, transmitting the
depolarization signal uniformly throughout the cell.
From depolarization to contraction
Proteins in the sarcolemma which forms the wall of the T-tubule change conformation, i.e.
they change their shape, in response to the excitation travelling over the sarcolemma. These
proteins are in touch with calcium channels which are embedded in the membrane of the
cisternae of the sarcoplasmatic reticulum. The change in the shape of the proteins belonging
17
Membrane potential (mV)
to the T-tubule opens the calcium channels of the sarcoplasmatic reticulum. Calcium can now
move from stores in the sarcoplasmatic reticulum into the cytoplasm surrounding the
myofilaments.
(a)
End-plate
potential (EPP)
0
B
Action Potential
-50
C
-100
A
Time (msec)
Nerve impulse stimulation
at axon terminal
(b)
T-tubules
Sarcolemma
In the resting phase Ca2+ is
retained in the Sarcoplasmic
reticulum
(Point A in schematic graph of
membrane potential)
-+ + + + + +-+
T-tubules
Sarcolemma
+ + + + +
- - - - - -
+ +
Ca2+
Sarcolemma
- - - - - - -
+ +
Sarcoplasmic
reticulum
+ +
+ +
+ + + + + +
- - - - - -
Sarcoplasmic
reticulum
Nerve impulse leads to
Polarity is restored when the
reversal of polarisation and
acetylcholine is broken down at
causes release of the Ca ions the neuromuscular junction. This
which bind to troponin and
releases the calcium back to the
lead to muscle contraction
sarcoplasmic reticulum.
(Point B on graph)
(Point C on graph)
Fig. 14a and b: Schematically showing the action potential at neuromuscular junction
Sites of interaction between actin and myosin are in resting muscle cells "hidden" by
tropomyosin. Tropomyosin is kept in place by a complex of proteins collectively called troponin.
The binding of calcium to troponin-C induces a conformational change in the troponintropomyosin complex, which permits the interaction between myosin and actin and, as a
consequence of this interaction, contraction. Contraction is regulated by calcium ion
concentration. In the resting state, a fiber keeps most of its intracellular calcium carefully
sequestered in an extensive system of vessicles known as the sarcoplasmic reticulum. There
are at least two receptors in the chain between depolarization and calcium release. Once
released, calcium binds to troponin, opening the myosin binding sites on filamentous actin,
and force is produced.
The interior of a resting muscle fiber has a resting potential of about −95 mV. The influx of
sodium ions reduces the charge, creating an end plate potential. If the end plate potential
reaches the threshold voltage (approximately −50 mV), sodium ions flow in with a rush and
an action potential is created in the fiber. The action potential sweeps down the length of the
18
fiber just as it does in an axon. No visible change occurs in the muscle fiber during (and
immediately following) the action potential. This period, called the latent period, lasts from
3–10 msec.
Before the latent period is over, the enzyme acetylcholinesterase breaks down the ACh in the
neuromuscular junction (at a speed of 25,000 molecules per second) and the sodium channels
close. And the junction is ready to receive another nerve impulse. The resting potential of the
fiber is restored by an outflow of potassium ions. The brief (1–2 msec) period needed to
restore the resting potential is called the refractory period. This entire sequence of events
starting from excitation by nerve impulse at the neuromuscular junction, which results in
physical contraction of the muscle is called as the excitation-contraction coupling
Excitation contraction coupling
Like most excitable cells, muscle fibers respond to the excitation signal with a rapid
depolarization, which is coupled with its physiological response: contraction. The spread of
excitation over the sarcolemma is mediated by voltage-gated ion channels. Invaginations of
the sarcolemma form the T-tubule system, which "leads" the excitation into the muscle fibre,
close to the border between the A- and I-bands of the myofibrils. Here, the T-tubules are in
close apposition with cisternae formed by the sarcoplasmatic reticulum. This association is
called a triad. The narrow gap between the T-tubule and the cisternae of the sarcoplasmatic
reticulum is spanned by proteins, which mediate the excitation-contraction coupling. In
summary, the generation of force is the result of stimulation of the motor nerve within a
motor unit, and the signal arrives at the muscle membrane through the motor end plate in all
the muscle fibers within the motor unit. The entire process is called Excitation-Contraction
Coupling. The activation of the nerve is the result of the summation of a series of small
electrical potentials. This summation can be temporal or spatial in nature. While two stimuli
independently may not have enough strength to elicit an impulse in a nerve or a muscle, if
they occur rapidly in time they may have an additive effect. Temporal summation involves
repetitive firing over a single nerve, whereas spatial summation involves timed firing over
multiple nerves. Finally, refractory period is the time when a nerve or muscle cell is
unresponsive to external stimuli. It has two separate phases: the absolute refractory period
where a cell cannot fire regardless of the stimulus strength, and the relative refractory period
when the excitable cell can respond with an impulse but only to a stiumulus larger than
normal. The concept of the refractory period only applies to the depolarization of the
sarcolemma, and not to the events that follow (calcium release channel activation, calcium
release, calcium-trponin interaction, cross bridge formation, power stroke).
Two basic types of contraction are isotonic and isometric
In an isotonic contraction the muscle shortens, keeping a constant tension. In an isometric
contraction the muscle does not shorten and tension builds up. Most real contractions are
mixtures of the two types.
A Single nerve impulse produces a muscle twitch
Single stimuli usually release enough acetylcholine in the neuromuscular junctions of the
motor unit to produce action potentials in the muscle membranes and the muscles then
contract after a short delay.
19
Order of events: ACh release -> muscle action potential -> Ca release -> contraction
A simple twitch gives only 20-30% of the maximum tension possible- the muscle starts to
relax before the maximum is reached (Fig. 15a). If a second stimulus is given before a muscle
relaxes the muscle will shorten further, building up more tension than a simple twitch- this is
called summation (Fig. 15b). At 5 stimulations per second, the individual twitches begin to
fuse together, a phenomenon called clonus. If many stimuli are given very close together (50
stimuli per second) the muscle will go into a smooth continuous contraction called tetanus
(Fig. 15c). Tetanus gives the maximum tension, about 4X higher than a simple twitch
(isometric contraction). Clonus and tetanus are possible because the refractory period is much
briefer than the time needed to complete a cycle of contraction and relaxation. The amount of
contraction is greater in clonus and tetanus than in a single twitch. Another way to increase
the force of contraction is to recruit more motor units. Each muscle is made up of tens of
thousands of motor units. Force generated by a muscle can be increased by firing more and
more motor units.
Fig. 15a: A muscle is stimulated at 0.5 seconds and again at 2.5 seconds; there is
complete relaxation between the stimuli and the tension reaches only 25% of maximum
(Madonna computer simulations of muscle contraction). It is assumed that tension is
proportional to the amount of Ca bound to troponin
Fig. 15b: The muscle is stimulated at 0.5 seconds and again at 0.7 seconds. The muscle
does not completely relax between stimuli and the tension summates to 35% of
maximum
20
Fig. 15c: The muscle was given 20 stimuli 0.1 seconds apart (lower trace). The
contractions fuse to produce a tetanus that rises to over 90% of maximum
Different types of skeletal muscle fibers specialize for endurance or speed
Skeletal muscles contain two types of fibers, which differ in the mechanism they use to
produce ATP; the amount of each type of fibre varies from muscle to muscle and from person
to person.
Endurance fibers (type I) or the Red muscle fibres: Red ("slow-twitch") fibers have more
mitochondria, store oxygen in myoglobin, rely on aerobic metabolism, and are associated
with endurance; these produce ATP more slowly. Marathoners tend to have more red fibers.
Have many mitochondria- the mitochondria give these fibers a red appearance because one of
the mitochondrial enzymes contains Fe. Also contain a red pigment called myoglobin, which
stores O2. Contract slowly but resist fatigue.
Fast twitch fibers (type II) or white muscle fibre: White ("fast-twitch") fibers have fewer
mitochondria, are capable of more powerful (but shorter) contractions, metabolize ATP more
quickly, and are more likely to accumulate lactic acid. Weightlifters and Sprinters tend to
have more white fibers. They contain few mitochondria. Relying on glycolysis to supply
energy (glycolysis is faster than respiration). Contract rapidly but fatigue quickly.
Comparison of different types of fibres is given in Table 2.
Table 2: Comparison of different types of skeletal muscle fibers
Fibre type
Type I fibres Type IIa fibres
Contraction time
Slow
Size of motor neuron Small
Resistance to fatigue High
Activity Used for
Aerobic
Force production
Low
Mitochondrial
High
density
Capillary density
High
Oxidative capacity High
Glycolytic capacity Low
Major storage fuel Triglycerides
Type IIb fibres
Fast
Large
Intermediate
Long-term anaerobic
High
High
Very fast
Very large
Low
Short-term anaerobic
Very high
Low
Intermediate
High
High
Creatine phosphate,
glycogen
Low
Low
High
Creatine phosphate,
glycogen
21
Intermediate lengths of filaments produce the most isometric strength
If you measure the isometric tension of a muscle when it is fixed at different lengths you will
find that there is an optimum length for producing tension. At rest many of the body's
muscles are close to their optimum lengths.There is a connection between the chemical
anatomy of actin and myosin and the amount of tension produced when they interact
The chemical connection is based upon two principles:
1) actin and myosin connect through crossbridges- the more crossbridges the more
tension. Suppose the muscle is stretched so far that actin and myosin hardly overlapthen there will be few crossbridges and little tension. As the muscle is shortened from
this extreme length more and more overlap will occur and the tension will rise.
2) when the muscle proteins interfere with crossbridges it will weaken the tension. If the
muscle is shortened too much the actin filaments will bump into each other and bendthis distorts the sarcomere and weaken the contraction
Metabolism of the muscle contraction
Energy for the reorientation and movement of the myosin head comes from the molecule
ATP. Oddly enough, stopping the process of muscle contraction also requires energy. The
saying 'it takes energy to relax', is certainly true for skeletal muscle. Muscle contraction stops
when Ca++ is removed from the immediate environment of the myofilaments. The
sarcoplasmic reticulum actively pumps Ca++ back into itself and this requires utilization of
ATP. Troponin-tropomyosin re-assume their inhibitory position between the actin and
myosin molecules once Ca++ is removed.
It is important to remember that the above scenario applies for groups of individual muscle
fibers, which with their motor neuron are called motor units. When a muscle is required to
contract during exercise not all motor units are used (or recruited). Most movements require
only a fraction of the total power available from an entire muscle. Consequently, our motor
system grades the intensity of muscle contraction by recruiting various numbers of motor
units. Even during maximal shortening contractions (so called concentric contractions) it is
doubtful that all motor units are recruited.
Energy supply for muscle contraction
ATP adenosine triphosphate (there are three phosphates in ATP) is the immediate source of
energy for muscle contraction. ATP is not stored to a great degree in cells. Once muscle
contraction starts the regeneration of ATP must occur rapidly. There are three primary
sources of high-energy phosphate for ATP replenishment, which in order of their utilization,
are creatine phosphate (CP), anaerobic glycolysis, and oxidative phosphorylation or cellular
respiration in the mitochondria of the muscle fibres.
Creatine phosphate
The phosphate group in creatine phosphate is attached by a "high-energy" bond like that in
ATP. Creatine phosphate derives its high-energy phosphate from ATP and can donate it back
to ADP to form ATP.
Creatine phosphate + ADP ↔ creatine + ATP
22
The pool of creatine phosphate in the fiber is about 10 times larger than that of ATP and thus
serves as a modest reservoir of ATP.
Glycogen
Skeletal muscle fibers contain about 1% glycogen. The muscle fiber can degrade this
glycogen by glycogenolysis producing glucose-1-phosphate. This enters the glycolytic
pathway to yield two molecules of ATP for each pair of lactic acid molecules produced. Not
much, but enough to keep the muscle functioning if it fails to receive sufficient oxygen to
meet its ATP needs by respiration. However, this source is limited and eventually the muscle
must depend on cellular respiration.
Cellular respiration
Cellular respiration not only is required to meet the ATP needs of a muscle engaged in
prolonged activity (thus causing more rapid and deeper breathing), but is also required
afterwards to enable the body to resynthesize glycogen from the lactic acid produced earlier
(deep breathing continues for a time after exercise is stopped). The body must repay its
oxygen debt.
ATP utilization in the muscle contraction
ATP is hence required for both contraction and relaxation of muscle. ATP is the energy
supply for contraction. It is required for the sliding of the filaments, which is accomplished
by a bending movement of the myosin heads. It is also required for the separation of actin and
myosin, which relaxes the muscle. When ATP runs down after death muscle goes into a state
of rigor mortis. In cardiac (heart) and smooth muscle special junctions help spread the
excitation from one cell to another muscle contractions require energy, which is supplied by
ATP. This energy is used to detach the myosin heads from the actin filaments. Because
myosin heads must attach and detach a number of times during a single muscle contraction,
muscle cells must have a continuous supply of ATP. Without ATP the myosin heads would
stay attached to the actin filaments, keeping muscles permanently contracted. A muscle
contraction, like a nerve impulse, is an all-or-none response- either fibers contract or they
remain relaxed. The force of a muscle contraction is determined by the number of muscle
fibers, that are stimulated. As more fibers are activated, the force of the contraction
increases. Some muscles, such as the muscles that hold the body in an upright position and
maintain posture, are nearly always at least partially contracted.
23
ATP hydrolysis for muscle contraction
The energy for muscle contraction comes from ATP hydrolysis (Fig. 16). ATP binds and the
head group detaches ATP. The latter is a direct consequence of the interaction between
myosin and actin. Actin catalyzes the ATPase activity of Myosin. The rate-limiting step is the
release of products of ATP hydrolysis (ADP and Pi). The Release of Pi results in tighter
binding and power stroke. These remain noncovalently bound to the myosin molecule and
prevent further ATP binding and hydrolysis. Release of ADP begins another cycle. The
binding of myosin to actin causes a rapid release of ADP and P from the myosin molecule.
Each cycle takes about 50 msec. Inability of myosin cross-bridges to detach in the absence of
ATP is basis for rigor mortis.
Fig. 16: ATP utilization during muscle contraction
ATP is synthesized via glycolysis in the sarcoplasm and/or via oxidative phosphorylation in
the mitochondria. Glycolysis may occur under anaerobic condition, the yield is 2 or 3
ATP/glucose. Oxidative phosphorylation provides 36 ATP/glucose. Also, dismutation of 2
ADP catalyzed by adenylate kinase yields 1 ATP + 1 AMP.
It is the globular head of the myosin molecule that binds to actin and hydrolyses ATP. Each
actin molecule in the thin filaments can bind one myosin head. The heads bind with the same
orientation to each actin subunit and thus point all in the same direction. The actin filament
has a plus- and a minus-end (compare this to microtubules). The latter points towards the
center of the sarcomere. The thin filaments on either side of the sarcomere are of opposite
polarity to accommodate the oriented myosin heads appropriately. The myosin heads point in
opposite directions away from the sarcomere center. The myosin heads walk from the minus
ends of the thin filaments in center of the sarcomere to the plus-ends on the Z-discs. During
this movement, ATP is hydrolysed and subsequent dissociation of the tightly bound products
(ADP and P) produce an ordered series of changes in the conformation of myosin, moving
the actin filaments along the thick filaments. The ATP concentration in muscle is quite low
(5-8 mmoles/g muscle), enough only for a few contractions. The used ATP is immediately
resynthesized from PCr. However, the PCr concentration is also low (20-25 mmoles/g),
24
enough for some additional contractions. Glycogen offers a rapid but still limited energy store
(endogenous glycogen concentration about 75 mmoles glucose units in glycogen/g muscle),
whereas oxidative phosphorylation is the slowest and most efficient process for ATP
production. For example, the glycogen store offers energy for a runner for about 1/2 hr and
oxidative phosphorylation for an additional 2 hrs.
Heat production during muscle contraction
The muscle converts the free energy of ATP into work and heat. According to the second law
of thermodynamics, in a system like muscle, which is at uniform temperature, it is impossible
to convert heat into work. (This is possible in steam engine, which is not at uniform
temperature, but there is a rather large temperature gradient within the engine). It follows that
in muscle the heat produced is a lost free energy and the efficiency of the muscle is the ratio
of the work produced to the free energy of ATP:
Efficiency = Work produced / Free energy of ATP
The chemical reactions occurring in muscle generate heat that is vital for maintaining body
temperature. Inversely, measuring heat in various phases of muscle contraction indicate the
existence of exothermic chemical reactions.
Representation of the Fenn effect
Heat production
D
C
B
A
Time marks: 0.2 sec
During isotonic contraction more heat is liberated than during isometric contraction. Fenn
called this extra heat the shortening heat. The shortening heat is proportional to the
shortening of the muscle; the larger the shortened distance, the more extra heat is produced
(this is called the Fenn effect). In this simplified representation of the Fenn effect, Line A
represents only isometric contraction. Lines B-D represent the time when the muscle was
contracting isometrically until it was released and allowed to shorten various distances. Fenn
gave his theory in 1923 and 1924 and this was further worked at by A.V Hill in 1938.
Relationship between work-output and O2 consumption: If work-output can be measured,
it can be converted into kcal equivalents. For example, on the bicycle ergometer with a
flywheel of 6 m and a pedaling rate of 50 RPM (300 m total distance per min) with 1 kg
resistance, 300kg.meter work is performed per min. Since 1 kg.meter corresponds to 0.00234
kcal, 300 kg.meter can be converted into 0.7 kcal of work-output. Assuming 25% efficiency,
the total energy expenditure per minute is 4 x 0.7 = 2.8 kcal. Since 4.8 kcal corresponds to 1liter O2 consumption, the 2.8 kcal is equivalent to 0.58-liter O2 consumption. (Note the
following terms: work = force x distance; force = mass x acceleration; power = work per unit
of time; energy = the capacity of performing work).
Many studies were carried out to relate different work-outputs under various conditions with
oxygen consumption, in healthy individuals and in patients. Such studies are helping
25
physicians to design programs for individuals to lose weight, improve athletic performance,
or to rehabilitate following muscle injury or heart disease.
With an increase in competitive sports, the study of sports medicine has become important.
The analysis of an individual performance has become increasingly complex and athletes are
put under scrutiny for their muscle performance, endurance as well as the physiological
relation to their genetic constitution. Even under conditions of microgravity, the effect of
muscle atrophy and fatigue have become important to determine the long term effect of space
travel on astronomers.
During an intense period of exercise, phosphocreatinine level has decreased and much of the
glycogen may have been converted to lactic acid. Oxygen debt is likely to be created. To
restore the normal cellular metabolite levels, energy is needed and the muscle utilizes oxygen
to provide energy for the cellular processes. The muscle continues to consume oxygen at a
high rate after it has ceased to contract. Therefore, we breathe deeply and rapidly for a period
of time, immediately following an intense period of exercise, repaying the oxygen debt.
Example for calculation of oxygen debt: After exercise, a total of 5.5 liters of O2 were
consumed in recovery until the resting value of 0.31 liter/min was reached. The recovery time
was 10 min.
Oxygen debt = 5.5 - (0.31 x 10) = 2.4 liters
It is customary to differentiate between high-intensity strength activities and low-intensity
endurance exercises. The different types of exercises elicit different patterns of neural
activity to muscle resulting in specific adaptation. High intensity strength activities, such as
weight lifting and bodybuilding, induce hypertrophy of the muscle with an increase in
strength. Endurance exercises, such as swimming and running, increase the capacity of
muscle for aerobic metabolism with an increase in endurance.
Muscle fatigue is defined as a loss of work-output leading to a reduced performance of a
given task. Fatigue may result from deleterious alterations in the muscle itself and/or from
changes in the neural input to the muscle. During prolonged endurance exercise, e.g.
marathon-running, depletion of muscle glycogen, decrease in blood glucose, dehydration, or
increase in body temperature contribute to fatigue. During intense muscular activity, e.g.
short-distance running, lactic acid is formed via anaerobic glycolysis. The H+ ions dissociated
from lactic acid decrease the pH of the muscle; this may inhibit metabolic processes, disturb
excitation-contraction coupling, Ca2+ fluxes, actomyosin ATPase activity, and thereby
decrease work output.
Disorders of skeletal muscle and smooth muscle
Disorders of the muscles could be acquired, familial, and congenital types. Some of the
common types of disorders are:
Compartment syndromes – It’s a condition where increased pressure within a limited space
compromises the circulation and function of tissue within that space. Compartmentation
involves mainly the leg but forearm, arm, thigh, shoulder, and buttock are also involved.
These lead to nerve compression, paralysis, and contracture. Some of the causes of increased
pressure are trauma, tight dressings, hemorrhage, and exercise.
26
Fibromyalgia – It is characterized by myalgia and multiple points of focal muscle tenderness
to palpation. Muscle pain is typically aggravated by inactivity or exposure to cold. This
condition is often associated with general symptoms, such as sleep disturbances, fatigue,
stiffness, headaches, and occasionally depression. Fibromyalgia may arise as a primary or
secondary disease process. It is most frequent in females aged 20 to 50 years.
Muscle cramp - A sustained and usually painful contraction of muscle fibers. This may
occur as an isolated phenomenon or as a manifestation of an underlying disease process e.g.,
uremia; hypothyroidism; motor neuron disease, etc.
Muscular dystrophies - The muscular disorders are a heterogenous group of inherited
disorders characterized clinically by progressively severe muscular weakness and wasting,
often beginning in childhood.
X-linked muscular dystrophies - The most well known of the muscular dystrophies is
Duchenne muscular dystrophy (DMD), followed by Becker muscular dystrophy (BMD).
They cause similar patterns of weakness and disability and are inherited in the same way,
although weakness and disability are more severe in DMD. Becker dystrophy is often
classified as a less severe form of Duchenne dystrophy. They both are due to defects of the
same gene, the normal function of which is to enable muscle fibers to make a particular
chemical substance, a protein called dystrophin. Muscle fibers in people affected with DMD
are extremely deficient in dystrophin, but in BMD the deficiency is less severe.
Myotonic disorders - Diseases characterized by myotonia, which may be inherited or
acquired. Myotonia may be restricted to certain muscles (e.g., intrinsic hand muscles) or
occur as a generalized condition. These disorders may be associated with abnormal muscle
sodium channel and chloride channels. Myotonic dystrophy and Myotonia congenita
represent two relatively common forms of this disorder. Proximal myotonic myopathy often
presents with myotonia and muscle pain in early adulthood and later in life thigh muscle
weakness and cataracts develop.
Myotonic dystrophy: An autosomal dominant neuromuscular disorder which usually presents
in early adulthood, characterized by progressive muscular atrophy (most frequently involving
the hands, forearms, and face), myotonia, frontal baldness, lenticular opacities, and testicular
atrophy. Cardiac conduction abnormalities, diaphragmatic weakness, and mild mental
retardation may also occur. Congenital myotonic dystrophy is a severe form of this disorder,
characterized by neonatal muscle hypotonia, feeding difficulties, respiratory muscle
weakness, and an increased incidence of mental retardation.
Myotonia congenita: A dominantly inherited muscle disease that begins in early childhood
and is characterized by severe myotonia (delayed relaxation of a muscle) after forceful
voluntary contractions. Muscular hypertrophy is common and myotonia may impair
ambulation and other movements. Myotonia typically becomes less severe with repetitive
voluntary contractions of the affected muscles. Generalized myotonia (of Becker) is an
autosomal recessive variant of myotonia congenita that may feature more severe myotonia
and muscle wasting.
27
Disease of neuromuscular junction
Myasthenia gravis
Myasthenia gravis (MG) is a chronic autoimmune disorder that results in progressive skeletal
muscle weakness. MG causes rapid fatigue (fatigability) and loss of strength upon exertion
that improves after rest. In early stages, myasthenia gravis primarily affects muscles that
control eye movement (extraocular muscles) and those that control facial expression,
chewing, and swallowing. If untreated, the disorder may affect muscles that control breathing
(respiration), causing acute respiratory failure. Autoantibodies directed against acetylcholine
receptors damage the motor endplate portion of the neuromuscular junction, impairing the
transmission of impulses to skeletal muscles.
Myasthenia gravis can be classified according to which skeletal muscles are affected:
Ocular myasthenia gravis: weakness only in muscles that control eye movement. About 10–
15% of patients are affected.
Generalized myasthenia gravis: Within a year of onset, approximately 85–90% of patients
develop which is characterized by weakness in the trunk, arms, and legs.
Congenital MG: An inherited condition, which develops at or shortly after birth and causes
generalized symptoms.
Transient neonatal MG: It is a temporary condition that develops in 10–20% of infants born
to mothers who have MG. Transient neonatal MG is caused by circulation of the mother's
antibodies through the placenta and it lasts as long as the mother's antibodies remain in the
infant (usually a few weeks after birth).
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