Chapter-3 Muscle Physiology

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Note: This is a brief notes so you may add more points referring to lectures, text book and other
web resources.
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Muscle functions (general):
Ability to use chemical energy to produce force and movement is present to a limited
extent in most cells, but in muscle cells it has become dominant (the effector).
.
1. Movements: Muscles make things happen. They supply force for movement and
together with the skeletal system are the movers and levers that make an act. Just as
importantly, muscle restraint motion. During a strong cough to clear the throat, 253
named muscles contract.
a) Purposeful movement of whole body or parts of body e.g. walking or waving
hands.
b) Manipulation of external objects e.g. speech, artistic expression, driving a car etc
c) Propulsion of contents through various hollow internal organs e.g. circulation of
blood, movement of materials through digestive tract
d) Emptying contents of certain organs to external environment e.g. urination,
defecation or giving birth.
2. Heat production : When muscles contract not all the energy is used for work, heat is
also produced. This heat constitutes an important part of maintaining body
temperature (homeostasis).
3. Posture: Partial contraction of skeletal help to maintain positions of body. When we
stand comfortably or sit reflectively, muscles hold our body in position to keep
it from toppling over.

Two by products of muscle contraction that usually go unnoticed are noise and very low
voltage of electricity. However, many shark and some other predaceous fishes have
sensory receptors that detect these stray noise and electric signals at close range. Even
when preys are hidden or buried their muscles contract to pump water across their gills
during regular breath. The electric noise from these contracting muscles can betray their
position to predators.
Modes of locomotion in animals:
 Fossorial: digging
 Arboreal (grip): climbing
 Scansorial (claws): climbing
 Saltatorial: jumping
 Aerial: flying
 Cursorial: rapid running, running long
Muscle composition:
 About 50% of body weight is muscles i.e. largest group of tissue.
 Skeletal muscle alone makes up about 40% of body weight in man and 32% in
woman.
 Smooth muscle and cardiac muscles contribute another 10%.
Muscle classification: Because muscles have many functions and many scientists from
diverse fields study them, muscles are classified with different criteria. Most commonly
used criteria are (fig 8-1)-
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1) Based on striations:
a) Striated muscles : Skeletal and Cardiac
b) Unstriated muscles : Smooth muscles
2) Based on control:
a) Voluntary muscles : Skeletal muscles
b) Involuntary muscles : Cardiac and smooth muscles
Although there are significant differences between these three types of muscles, the
force generating mechanism is similar in all of them.
3) Based Biochemistry:
(i) Slow oxidative (ii) Fast oxidative and (iii) Fast glycolytic

Skeletal muscle structure (general):

All muscle cells come with standard cellular equipment, viz nuclei, mitochondria and like
but specialized terms have grown up for familiar cell organelles.
 Skeletal muscles are stimulated to contract by release of acetylcholine (Ach) at
neuromuscular junction between motor terminal and muscle cell.
 To understand this mechanism of muscle contraction, a basic understanding of
structural components is essential (study fig 8-2, 8-3, 8-4, 8-5, 8-6, 8-7, 8-9, 8-10,
8-12, 8-13).
 A single skeletal muscle cell is known as muscle fiber
 Relatively large about 10-100m in diameter and upto 2.5 feet in length (human)
 Each cell or fiber is multinucleated tube with many myofibrils packed together
 Cell membrane folds in to form sarcolemma
 A myofibril contains thick filaments of protein myosin and thin filaments of protein
actin
 Repeated, high-intensity, short exercise cause synthesis of additional actin and
myosin filaments
 Endurance exercise develops more mitochondria, myoglobin and capillaries

Summary of level of organization in a skeletal muscle (fig8-2):

Whole muscle thick and thin myosin and

Muscle  fiber  myofibril  filaments  actin
(organ) (cell) (specialised (cytoskeletal) (motor proteins)
intracellular
structure)
Sarcomere (fig 8-2):
a. The area between two Z line-a function unit of skeletal muscle- capable of
contraction.
b. Z-line connects thin filaments of two adjoining sarcomeres
c. Relaxed sarcomere is about 2.5 m in width
d. During muscle growth muscle increases in length by adding new sarcomere but
not by increasing size of each sarcomere

Thick filaments and myosin (fig 8-4):

 12-18nm in diameter and 1.6m in length.
 Each thick filament is made of myosin molecules packed together in bundle

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 Each myosin molecule has two polypeptide chains, each having a golf-club-
shaped subunits (cross-bridge).
 Tails intertwined (heavy chain) and globular heads (cross- bridge)
 Each cross-bridge contains actin binding site and ATP binding site
 The double heads of each myosin molecule face outward from center of filament
 The head acts as molecular cross bridges that interact with the thin filaments in
contraction
Thin filaments : (fig 8-5)
 5-8nm in diameter and 1.0m long.
 Thin filaments are composed of three different proteins
 The backbone is a double strand of actin twisted into a double helix
 Surrounding the actin filament are two strands of tropomyosin that lie in the
groves of actin
 Each tropomyosin is a double helix
 The third protein of thin filament is troponin, a complex of three globular proteins
 Thread like tropomyosin molecules are arranged in ribbon form that lies alongside
the groove of actin helix covering binding sites on actin molecules for attachment
with myosin cross-bridges.
 Troponin is a calcium-dependent switch that acts as the control point in
contraction (fig 8-6)

ATP-powered cross-bridge cycling: (fig 8-6 to 8-8 & 8-12)

According to this model, myosin filament and actin filaments link together by
molecular cross-bridges in presence of Ca++ and energy ATP.
Step 1: Energized
ATP split by myosin ATPase; ADP and Pi remain attached to myosin; energy stored
in cross bridge. (If no excitation; no Ca released; actin and myosin prevented from
binding; no cross-bridge cycle; muscle fibers remains at rest).
Step-2: Binding
Ca++ released on excitation; removes inhibitory influence from actin, enabling it to
bind with cross bridge.
Step-3 : Power stroke (bending)
Power stroke of cross bridge triggered on contact between myosin and actin; Pi
released during and ADP released after power stroke.
Step 4: New ATP binds & Detachment
Linkage between actin and myosin broken as fresh molecule of ATP binds to myosin
cross bridge; cross bridge assumes original conformation; ATP hydrolyzed (cycle
starts again at step-1). (if no fresh ATP available, after death, actin and myosin
remain bound in rigor complex).

ATP performs two important functions:

a. The energy released from ATP hydrolysis ultimately provides the energy for
cross-bridge movement.
b. ATP binding to myosin breaks the link formed between actin & myosin
during the cycle, allowing the cycle to repeat.
Rigor mortis: It is the stiffening of skeletal muscles that begins several hours after death
and is completed after about 12hrs. The ATP concentration in a cell, including
muscles, declines after death because the nutrients & oxygen the metabolic pathways
require to form ATP are no longer supplied by the circulation. In the absence of
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ATP, the link breakage between actin & myosin does not occur. The thick & thin
filaments remain bound to each other by immobilized cross-bridges, producing a
rigid condition (fig 8-12). The stiffness of rigor mortis disappears about 48-60 hrs
after death as the muscle tissue disintegrates.

Role of tropomyosin, troponin & calcium in muscle contraction: (Fig. 8-5 & 8-6)
 Tropomyosin is a rod shaped molecule composed of intertwined polypeptides with a
length approximately equal to that of 7 actin molecules. Tropomyosin partially
covers the myosin binding site on each actin molecule, thereby preventing the cross-
bridges from making contact with actin. Each tropomyosin molecule is held in this
blocking position by the smaller globular protein troponin.
 Troponin, which interacts with both actin & tropomyosin. Troponin binds to
tropomyosin and regulates the access to myosin binding sites on actin molecules.
 Calcium binds to a specific binding site on the troponin. The binding of calcium
produces a change in shape of troponin, which drags tropomyosin away from the
myosin binding site on actin molecules. Conversely, the removal of calcium from
troponin reverses the process, turning off contractile activity.

Excitation-contraction (EC) coupling mechanism:

It refers to series of events by which an action potential in plasma membrane of a muscle
fiber leads to cross-bridge activities (sliding of filaments, shortening of sarcomere)
Stepwise EC coupling mechanism and involved structures and molecules are shown in
fig. 8-11. Important structures and molecules include-

1) Neuro-muscular junction (NMJ):

It is a functional connection (synapse) between neuron and skeletal muscle. Each muscle
fiber receives a single axon terminal from somatic motor neuron. Specialized region of
sarcolemma of muscle fiber at neuromuscular junction is known as a motor end plate

 Its role is to release of acetylcholine from nerve terminal to generates end plate
potential (action potential of muscle, a type of graded potential- recall previous
lectures!) at motor end plate (part of sarcolemma)
2) Acetylcholine (Ach) neurotransmitter produced at neuromuscular junction
 Ach binds to end plate receptors and generate end plate potential to initiate
muscle action potential
3) Transverse (T) tubule: At each junction of A- and I- band, surface membrane dips into
muscle fiber to form transverse tubule (T-tubule, fig 8-9)
 Provide a means of rapidly transmitting surface electric activity into central
portion of fiber
 Presence of local action potential in T-tubules induces calcium release from the
lateral sacs of sarcoplasmic reticulum through dihydropyridine receptors and
ryanodine receptors (fig 8-10).
4) Sarcoplasmic reticulum: Modified endoplasmic reticulum (fig 8-9).
 Stores Ca++. Spreading of action potential down a T tubule, triggers release of
Ca++ from lateral sacs of sarcoplasmic reticulum into cytosol
5) Calcium ions :
 Calcium is the link between excitation and contraction.

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 Ca exposes binding sites on actin
++

 Exposed sites of actin link with cross-bridges of myosin

Steps of Excitation-Contraction Coupling and relaxation: (fig 8-11)

Neuronal activation of skeletal muscle involves a sequence of events. Understanding the

steps in this sequence helps determine the locus of disruption that is affected by drugs or
diseases.

1. Ach released from terminal of motor neuron initiates action potential at motor end
plate of muscle cell that is propagated over entire surface of sarcolemma
2. Surface electrical activity is carried into central portions of muscle fibers by T-
tubules
3. This event induces dihydropyridine receptors to pull open ryanodine receptor
channels (p266; fig 8-10), allowing release of calcium from lateral sacs of
sarcoplasmic reticulum
4. Released Ca++ binds to troponin on thin filaments causing tropomyosin to move
away from the blocking position to expose actin binding sites
5. Energized myosin cross-bridge on the thick filaments bind to actin molecule
6. Angular movement of cross bridges produces power stroke that pulls thin filament
inward (muscle contraction)
7. ADP and Pi are released from cross bridge during power stroke
8. Fresh ATP molecule binding to myosin permits detachment of cross bridge,
which returns to original conformation
9. Splitting of new ATP molecule by myosin ATPase energizes cross-bridge once
again
10. If Ca++ is still present, cross bridges go through another cycle of binding and
bending, pulling thin filaments even further
11. Cytosolic calcium concentration decreases as calcium-ATPase actively transports
calcium into sarcoplasmic reticulum.
12. Removal of calcium from troponin restores blocking actions of tropomyosin, the
cross-bridge cycle ceases, and the muscle fiber relaxes.

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Steps of EC coupling are presented as a concept map:

Curare-
arrowhead
Motor nerve AP poison
MOTOR (blocks Ach sites)
N Release of Ach
E
R Binding Ach to receptors
V Diffusion of Ach
E across end plate
End plate Potential

AP on Sarcolemma
M
U
Depolarization of T-tubules S
Facilitates C
Caffeine Release of Ca++ from SR U
L
cytoplasmic Ca++ conc. E

Dis-inhibition of troponin-tropomyosin

Action of ATPase at cross-bridge

Force generation or muscle contraction

Skeletal Muscle Mechanics

Contractions of whole muscle can be of varying strength i.e. you can vary the force you
exert by the same muscle depending on whether you are picking up a paper, a book or
20kg bag of fertilizer.
Two primary factors which can be adjusted to accomplish gradation of whole-muscle
tension-
• Number of muscle fibers contracting within a muscle (motor unit recruitment)
• Tension developed by each contracting fiber

Motor unit recruitment:

The greater the number of fibers contracting, the greater is the total muscle tension. One
motor neuron innervates a number of muscle fibers. When a motor neuron is activated, all
the muscle fibers it supplies are stimulated to contract simultaneously. This team of
concurrently activated components-one motor neuron plus all the muscle fibers it
innervates-is called a motor unit (fig 8-18, 8-19).

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 Motor units involved in precise, delicate movements would have a small number of
muscle fibers (as few as a dozen). e.g. those that move the fingers for writing,
drawing, identifying and correcting faults in a machine by technician, movement of
eye etc.
o This gives a nervous system the option of making very tiny (fine) adjustments
in the performance of these muscles.
 Those units involved in powerful, coarsely controlled movement would have many
muscle fibers (1500-2000). e.g. those that control the postural muscles in the back or
rough vigorous exercise for jumping (gastrocnemius muscle), boxing (biceps muscle).
o Recruitment of motor units in these muscle results in large incremental
increases in whole muscle tension. More powerful contractions occur at the
expense of less precisely controlled gradation (fig 8-19).

For stronger and stronger contractions, more and more units are recruited or stimulated to
contract, a phenomenon known as motor unit recruitment.

Asynchronous recruitment of motor unit- The body alternates motor activity to give
motor units that have been active an opportunity to rest while others take rest. This is
possible only for submaximal contractions, during which only some of the motor
units maintain the desired level of tension. During maximal contractions, when all
muscle fibers must participate, it is impossible to alternate motor unit activity to
prevent fatigue. This is one reason why you cannot support a heavy object as long as
a light one.

Muscle Twitch:
The graphical picture of mechanical response of a single muscle fiber to a single AP is
known as a twitch or simple muscle curve (SMC) fig 8-13. The onset of the resulting
contractile response lags behind the AP because of its propagation of in the motor nerve
and the entire excitation-contraction coupling mechanism occur before cross-bridge
activity begins. This time delay of a few milliseconds between stimulation and the onset
of contraction is known as latent period The time interval from the beginning of tension
development to the peak of tension is the contraction time- the active phase. The curve
passively assumes the base line is the relaxation period. In this phase, the transfer of
calcium ions to the sarcoplasmic reticulum inhibits the cross-bridge activities followed by
actin and myosin return to their normal position and length. The duration of entire twitch
is upto 100msec or more which is longer than the duration of AP (1-2msec). Normally
twitch contraction (SMC) is not occurring in skeletal muscles of the body.
 Study the phenomenon of summation and tetanus; page no. 8-20
 Fatigue: Decrease in muscle tension with prolonged activity.
Muscle tension
Muscle tension is transmitted to bones as the contractile component tightens the series-
elastic component (a stretchy spring placed between the internal tension generating
elements and the bones that is moved against an external load (fig 8-14, 8-17).

Skeletal Muscle Metabolism and fiber types

Muscle fibers have alternate pathways for forming ATP (fig 8-22):
ATP (oxidative phosphorylation), creatine-phosphate and glycogen supply energy for
muscle contraction.
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a. ATP performs three functions directly related to muscle fiber contraction and
relaxation.
1. Splitting of ATP by myosin-ATPase provides energy for power stroke of cross-
bridge
2. Binding (but not splitting) of fresh ATP to myosin permits detachment of bridge
between actin filaments to repeat the cycle. This ATP splits and provides energy
for next stoke of cross-bridge
3. Active transport for restoring the Ca++ back into SR requires ATP
The small supply of preformed ATP that exists at the start of contractile activity would
support a few twitches. If a fiber is to sustain contractile activity, metabolism must
produce molecules of ATP at rapid rate. There are three pathways fiber can form ATP.
1. Transfer of high-energy phosphate from creatine phosphate to ADP
2. Oxidative phosphorylartion in mitochondria (TCA cycle and electron transport
system)
3. Glycolytic pathway in cytoplasm.
b. Creatine-phosphate is a high-energy phosphate compound that stores bond energy
while at rest
 Creatine phosphate releases stored bond energy to convert ADP to ATP in the
reaction:
Creatine kinase
Creatine phosphate + ADP ATP + Creatine
 Within a few to 30 seconds, reserve of creatine phosphate is depleted.
c. Glycogen is the largest store of energy
 Glycogen is a chain of glucose molecules and is stored in liver and muscle
 Glycogen is abundant, can be mobilized quickly and provides energy under
anoxic conditions
 As creatine phosphate declines, enzymes convert glycogen to glucose-6-
phosphate
 This first stage of glycolysis proceeds into mitochondrial respiration and
generates 36 ATP
 If muscle contraction is moderate (not too vigorous or prolonged), glucose is
completely oxidized to carbon dioxide by aerobic respiration during the first 5
to 10 minutes of exercise.
 If the intensity of exercise is prolonged, blood cannot provide enough oxygen for
complete oxidation.
 The contractile machinery must then receive energy from anaerobic glycolysis
 Without anaerobic glycolysis, all heavy muscular exertion would be impossible
 Anaerobic glycolysis degrades glucose to lactic acid; energy released is used to
regenerate creatine phosphate.
 Lactic acid accumulates in muscle and diffuses into general circulation.
 Continued muscular exertion causes a buildup of lactic acid that leads to fatigue
 Muscle incurs an Oxygen debt because accumulated lactic acid must be
oxidized by extra oxygen.
 Oxygen consumption must remain elevated (extra oxygen) until all lactic acid has
been oxidized and return the blood and intestinal fluid oxygen to pre-exercise
values (example of negative feedback mechanism).

Muscle fatigue:

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 On repeated skeletal muscle stimulation, the tension the fibers develop eventually
decreases even though the stimulation continues. This decline in muscle tension
as a result of previous contractile activity is known as muscle fatigue.
 Many factors contribute to the fatigue of skeletal muscles; a few of them are-
 Conduction failure, Lactic acid build up, Inhibition of cross bridge cycling,
central command fatigue.
 Increased oxygen consumption is necessary to recover from fatigue (oxygen
debt).

Three types of skeletal muscles based on differences in ATP hydrolysis & synthesis
(biochemistry):

Skeletal muscle fibers do not all have the same mechanical and metabolic characteristics.
Different types of fibers can be identified on the basis of (1) their speed of shortening-
fast or slow- and (2) the major pathway they use to form ATP- oxidative or glycolytic
(table 8-1; 8-23a & b). Thus biochemically there are 3 types of muscle fibers (do not
confuse with three types of muscles that is given at the beginning of this note!).
a. Slow-oxidative (type-I) fibers are specialized for slow, sustained contraction
without fatigue (eg posture muscles of back)
 Slow fibers constitute red muscles because they contain a rich blood supply, a
high density of mitochondria, and abundant stored myoglobin oxygen reserves
b. Two kinds of fast fibers provide fast, powerful contractions
c. One type of fast fiber- Fast-oxidative (type IIA) fiber- has extensive blood supply,
mitochondria and myoglobin and functions aerobically and can sustain exercise
for long periods of time
 Dogs and ungulates have limb muscles with a high percentage of fast aerobic
fibers
d. Second kind of fiber Fast-glycolytic (Type-IIX)- lacks efficient blood supply and
high density of mitochondria and myoglobin; they are pale in colour and, function
anaerobically and fatigue rapidly
 White meat of chicken is an example of this fast fiber muscle
 The canine (cat family) has running muscles made up almost entirely of fast
fibers that operate anaerobically.
 Such muscles rapidly build up an oxygen debt; cheetah must rest 30-40
minutes after a chase.

Adaptation of muscles during exercise & training:

The regularity in use and duration & intensity of muscle activities affect the properties of
the muscles (A closer look at Exercise Physiology on page 284).
 Maximum O2 uptake during strenuous exercise, about 50ml of O2 per minute per
kg body weight in male between 20-25 years of age
 Trained endurance athletes (swimmers or long distance runners) maximum O2
uptake can be 86 ml/minute/kg body weight wt. Lactate will produce and muscles
develop fatigue
 Since depletion of muscle glycogen places a limit on exercise, any adaptation that
spares muscle glycogen will improve physical endurance
Effect of endurance training:
 Improved ability to obtain ATP from oxidative phosphorylation
 Increased size and number of mitochondria
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 Less lactic acid produced per given amount of exercise
 Increased myoglobin content; Increased muscular triglyceride content
 Increased lipoprotein lipase (to utilize lipids from blood)
 Increased proportion of energy derived from fat, less from carbohydrate
 Lower rate of glycogen depletion during exercise
 Improved efficiency of in extracting O2 from blood
 Decreased number of fast glycolytic fibers and increased number of fast oxidative
fibers.
Testosterone influence:
o Men’s muscle fibers are thicker, larger and stronger than those of women, even
without training because of action of testosterone, a steroid hormone secreted
primarily in males.
o Testosterone promotes the synthesis and assembly of myosin and actin-larger
muscle mass (hypertrophy). This fact has led some athletes, both males and
females, to the dangerous practice of taking testosterone or other closely related
anabolic steroids to increase their athletic performance.

Muscular pathophysiology: Injuries & diseases of muscles and associated

structures:
Muscle strains and tears (e.g. pulled hamstring) most commonly occur because of what is
called an "eccentric contraction." When this occurs, the muscle is trying to contract while
another force (the ground, another player, etc.) is forcing the muscle in the opposite
direction. This creates tremendous force on the muscle, and if the force is strong enough,
it will tear the muscle fibers.
Muscular Dystrophy: Involves progressive muscular wasting and usually results in death
by age of 20 from respiratory and cardiac failure. It’s a sex linked recessive disease.
Paralysis:
 Damage to spinal nerves or cell bodies of lower motor neuron (by Polio virus)
produces Flaccid paralysis. There is reduced muscle tone, depressed stretch reflexes
and atrophy of muscles.
 Amyotrophic lateral sclerosis (ALS) : Involves degeneration of lower neurons,
leading to muscle paralysis. Well-known Physicist Steven Hawking is the victim of
this disease. This is also an inherited disease caused by a defect in gene for enzyme
Superoxide dismutase. Normally this enzyme eliminates superoxide free radicals
which are highly toxic to damage motor neuron.

 Tetanus toxins and Botulinum toxins: bacterial products that cause paralysis by
preventing synaptic transmission at neuromuscular junction (recall last chapter
lectures!).
 Neurotoxins function as protease (protein digesting enzyme) digesting
component of fusion complex thus prevents release of neurotransmitters.
Botulinum toxin is used as treatment to relieve muscle spasm due to excessive
nerve stimulation. e.g. injected into affected extraocular muscle in order to
help correct strabismus (deviation of eye).
Comparative physiology of smooth and cardiac muscles (table 8-3):

Cardiac Muscle:
 Found only in the heart wall (fig 9-6), shares structural and functional similarities
with both skeletal and smooth muscles.

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 Myocardial cells are interconnected by gap junction (intercalated disc) that
enhances the speed of action potential throughout the heart.
 Cardiac muscles generate their own action potential (pacemaker).
 Not showing the properties of summation, tetanus and fatigue. This is because of
long refractory period 250 msec as long as contraction period (300 msec) of
cardiac muscle-is a protective mechanism for rhythmic pumping of blood.
(details functions will be discussed in the next chapter).

Smooth Muscle:

Actin and myosin filaments are not arranged in an orderly pattern (fig 8-28). Activation
of smooth muscle contraction pathways leading from increased cytosolic calcium to
cross-bridge cycle are illustrated in fig 8-29 & 8-30.
Smooth muscle is slow and economical:
 Contraction period is longest among all 3 muscles - is about 3 seconds.
 Rate of ATP splitting is slow, so cross-bridge and sliding occur more slowly.
 Also smooth muscle relaxes more slowly because a slower rate of Ca++ removal.
 Because of low rate of cross-bridge cycles, cross-bridges are maintained in the
attached state for longer period of time during each cycle.
 This latch phenomenon enables smooth muscle to maintain tension with
comparatively less ATP consumption.
 Thus, smooth muscles are economical contractile tissue, found in walls of hollow
organs (blood vessels, digestive tract etc) where long term sustained contractions are
going on with little energy consumption and without fatigue.

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Dr. Ketan Christi