Skeletal Muscle Physiology

Muscular System Functions

Body movement (Locomotion)
Maintenance of posture
Respiration
Diaphragm and intercostal contractions
Communication (Verbal and Facial)
Constriction of organs and vessels
Peristalsis of intestinal tract
Vasoconstriction of b.v. and other structures (pupils)
Heart beat
Production of body heat (Thermogenesis)
 Properties of Muscle
Excitability: capacity of muscle to respond
to a stimulus
Contractility: ability of a muscle to shorten
and generate pulling force
Extensibility: muscle can be stretched back
to its original length
Elasticity: ability of muscle to recoil to
original resting length after stretched
 Types of Muscle
Skeletal
Attached to bones
Makes up 40% of body weight
Responsible for locomotion, facial expressions, posture, respiratory movements,
other types of body movement
Voluntary in action; controlled by somatic motor neurons
Smooth
In the walls of hollow organs, blood vessels, eye, glands, uterus, skin
Some functions: propel urine, mix food in digestive tract, dilating/constricting
pupils, regulating blood flow,
In some locations, autorhythmic
Controlled involuntarily by endocrine and autonomic nervous systems
Cardiac
Heart: major source of movement of blood
Autorhythmic
Controlled involuntarily by endocrine and autonomic nervous systems
 Connective Tissue Sheaths
Connective Tissue of a Muscle
Epimysium. Dense regular c.t. surrounding entire muscle
Separates muscle from surrounding tissues and organs
Connected to the deep fascia
Perimysium. Collagen and elastic fibers surrounding a group of
muscle fibers called a fascicle
Contains b.v and nerves
Endomysium. Loose connective tissue that surrounds individual
muscle fibers
Also contains b.v., nerves, and satellite cells (embryonic stem cells
function in repair of muscle tissue
Collagen fibers of all 3 layers come together at each end
of muscle to form a tendon or aponeurosis.
 Nerve and Blood Vessel Supply

Motor neurons
stimulate muscle fibers to contract
Neuron axons branch so that each muscle fiber (muscle cell) is
innervated
Form a neuromuscular junction (= myoneural junction)
Capillary beds surround muscle fibers
Muscles require large amts of energy
Extensive vascular network delivers necessary oxygen
and nutrients and carries away metabolic waste
produced by muscle fibers
Muscle Tissue Types
 Skeletal Muscle
Long cylindrical cells
Many nuclei per cell
Striated
Voluntary
Rapid contractions
Basic Features of a Skeletal Muscle
Muscle attachments
Most skeletal muscles
run from one bone to
another
One bone will move
other bone remains fixed
Origin less movable
attach- ment
Insertion more
movable attach- ment
 Basic Features of a Skeletal
Muscle
Muscle attachments (continued)
Muscles attach to origins and insertions by
connective tissue
Fleshy attachments connective tissue fibers are
short
Indirect attachments connective tissue forms a
tendon or aponeurosis
Bone markings present where tendons meet
bones
Tubercles, trochanters, and crests
Skeletal Muscle Structure
Composed of muscle cells (fibers),
connective tissue, blood vessels, nerves
Fibers are long, cylindrical, and
multinucleated
Tend to be smaller diameter in small
muscles and larger in large muscles. 1
mm- 4 cm in length
Develop from myoblasts; numbers
remain constant
Striated appearance
Nuclei are peripherally located
Muscle Attachments
Antagonistic Muscles
Microanatomy of Skeletal
Muscle
 Muscle Fiber Anatomy
Sarcolemma - cell membrane
Surrounds the sarcoplasm (cytoplasm of fiber)
Contains many of the same organelles seen in other cells
An abundance of the oxygen-binding protein myoglobin
Punctuated by openings called the transverse tubules (T-tubules)
Narrow tubes that extend into the sarcoplasm at right angles to the
surface
Filled with extracellular fluid
Myofibrils -cylindrical structures within muscle fiber
Are bundles of protein filaments (=myofilaments)
Two types of myofilaments
1. Actin filaments (thin filaments)
2. Myosin filaments (thick filaments)
At each end of the fiber, myofibrils are anchored to the inner surface of
the sarcolemma
When myofibril shortens, muscle shortens (contracts)
 Sarcoplasmic Reticulum (SR)
SR is an elaborate, smooth endoplasmic reticulum
runs longitudinally and surrounds each myofibril
Form chambers called terminal cisternae on either side
of the T-tubules
A single T-tubule and the 2 terminal cisternae form
a triad
SR stores Ca++ when muscle not contracting
When stimulated, calcium released into sarcoplasm
SR membrane has Ca++ pumps that function to pump
Ca++ out of the sarcoplasm back into the SR after
contraction
Sarcoplasmic Reticulum (SR)
Parts of a Muscle
 Sarcomere - repeating functional units of a
myofibril
Sarcomeres: Z About 10,000 sarcomeres per myofibril,
end to end
Disk to Z Disk Each is about 2 m long
Differences in size, density, and distribution
of thick and thin filaments gives the muscle
fiber a banded or striated appearance.
A bands: a dark band; full length of thick
(myosin) filament
M line - protein to which myosins attach
H zone - thick but NO thin filaments
I bands: a light band; from Z disks to ends of
thick filaments
Thin but NO thick filaments
Extends from A band of one sarcomere to A
band of the next sarcomere
Z disk: filamentous network of protein. Serves
as attachment for actin myofilaments
Titin filaments: elastic chains of amino acids;
keep thick and thin filaments in proper
alignment
Structure of Actin and Myosin
 Many elongated myosin molecules shaped
like golf clubs.

Myosin (Thick) Single filament contains roughly 300
myosin molecules
Molecule consists of two heavy myosin
Myofilament molecules wound together to form a rod
portion lying parallel to the myosin
myofilament and two heads that extend
laterally.
Myosin heads
1. Can bind to active sites on the actin
molecules to form cross-bridges.
(Actin binding site)
2. Attached to the rod portion by a hinge
region that can bend and straighten
during contraction.
3. Have ATPase activity: activity that
breaks down adenosine triphosphate
(ATP), releasing energy. Part of the
energy is used to bend the hinge
region of the myosin molecule during
contraction
 Thin Filament: composed of 3 major
proteins
1. F (fibrous) actin
2. Tropomyosin Actin (Thin)
3. Troponin
Two strands of fibrous (F) actin form a
double helix extending the length of the
Myofilaments
myofilament; attached at either end at
sarcomere.
Composed of G actin monomers
each of which has a myosin-binding
site (see yellow dot)
Actin site can bind myosin during
muscle contraction.
Tropomyosin: an elongated protein
winds along the groove of the F actin
double helix.
Troponin is composed of three subunits:
Tn-A : binds to actin
Tn-T :binds to tropomyosin,
Tn-C :binds to calcium ions.
Now, putting it all together to perform the function
of muscle: Contraction
Z line Z line
H Band
Sarcomere Relaxed
Sarcomere Partially Contracted
Sarcomere Completely
Contracted
Binding Site Tropomyosin
Ca2+

Troponin
Myosin
 Excitation-Contraction Coupling

Muscle contraction

Alpha motor neurons release Ach

ACh produces large EPSP in muscle fibers (via
nicotinic Ach receptors
EPSP evokes action potential
Action potential (excitation) triggers Ca2+
release, leads to fiber contraction
Relaxation, Ca2+ levels lowered by organelle
reuptake
Excitation-Contraction Coupling
Excitation-Contraction Coupling
 Sliding Filament Model of
Contraction
Thin filaments slide past the thick ones so
that the actin and myosin filaments overlap
to a greater degree
In the relaxed state, thin and thick filaments
overlap only slightly
Upon stimulation, myosin heads bind to
actin and sliding begins
How striated muscle works: The Sliding Filament Model

The lever movement drives displacement of the actin filament relative to the myosin
head (~5 nm), and by deforming internal elastic structures, produces force (~5 pN).
Thick and thin filaments interdigitate and slide relative to each other.
Neuromuscular Junction
 Neuromuscular Junction
Region where the motor neuron stimulates the muscle fiber
The neuromuscular junction is formed by :
1. End of motor neuron axon (axon terminal)
Terminals have small membranous sacs (synaptic vesicles) that
contain the neurotransmitter acetylcholine (ACh)
2. The motor end plate of a muscle
A specific part of the sarcolemma that contains ACh receptors
Though exceedingly close, axonal ends and muscle fibers
are always separated by a space called the synaptic cleft
Neuromuscular Junction
 Motor Unit: The Nerve-Muscle
Functional Unit
A motor unit is a motor neuron and all the
muscle fibers it supplies
The number of muscle fibers per motor unit can
vary from a few (4-6) to hundreds (1200-1500)
Muscles that control fine movements (fingers,
eyes) have small motor units
Large weight-bearing muscles (thighs, hips) have
large motor units
 Motor Unit: The Nerve-Muscle
Functional Unit

Muscle fibers from a motor unit are spread

throughout the muscle
Not confined to one fascicle
Therefore, contraction of a single motor unit causes
weak contraction of the entire muscle
Stronger and stronger contractions of a muscle
require more and more motor units being stimulated
(recruited)
 Motor Unit
All the muscle cells controlled by one
nerve cell
Acetylcholine Opens Na+
Channel
 Muscle Contraction Summary

Nerve impulse reaches myoneural junction

Acetylcholine is released from motor
neuron
Ach binds with receptors in the muscle
membrane to allow sodium to enter
Sodium influx will generate an action
potential in the sarcolemma
Muscle Contraction (Contd)
Action potential travels down T tubule
Sarcoplamic reticulum releases calcium
Calcium binds with troponin to move the
troponin, tropomyosin complex
Binding sites in the actin filament are
exposed
 Muscle Contraction (contd)

Myosin head attach to binding sites and

create a power stroke
ATP detaches myosin heads and energizes
them for another contaction
When action potentials cease the muscle
stop contracting
Contraction Speed
Myosin is a Molecular Motor Myosin is a hexamer:
2 myosin heavy chains
4 myosin light chains
Coiled coil of two a helices

2 nm
C terminus

Myosin head: retains all of the motor functions of myosin,

i.e. the ability to produce movement and force.

Nucleotide
binding site

Myosin S1 fragment
crystal structure

NH2-terminal catalytic neck region/lever arm Ruegg et al., (2002)

(motor) domain News Physiol Sci 17:213-218.
Chemomechanical coupling conversion of chemical energy
(ATP about 7 kcal x mole-1) into force/movement.

ATP is unstable thermodynamically

Two most energetically favorable steps:
1. ATP binding to myosin
2. Phosphate release from myosin
Rate of cycling determined by MATPase activity and external load
Adapted from Goldman & Brenner (1987) Ann Rev Physiol 49:629-636.
Shortening Velocity Vependent on ATPase Activity
Different myosin heavy chains (MHCs) have different ATPase activities.
There are at least 7 separate skeletal muscle MHC genesarranged in series
on chromosome 17.
Two cardiac MHC genes located in tandem on chromosome 14.
The slow b cardiac MHC is the predominant gene expressed in slow fibers
of mammals.

Goldspink (1999) J Anat 194:323-334.

 Power Output: The Most Physiologically Relevant
Marker of Performance
Power = work / time
= force x distance / time
= force x velocity

Peak power obtained at intermediate loads and intermediate

velocities. Figure from Berne and Levy, Physiology
MosbyYear Book, Inc., 1993.
Three Potential Actions During Muscle Contraction:

Biceps muscle shortens

during contraction
shortening (Isotonic: shortening against fixed
load, speed dependent on
MATPase activity and load)

isometric

Most likely to cause

lengthening Biceps muscle lengthens
muscle injury
during contraction
 Motor Unit Ratios
Back muscles
1:100
Finger muscles
1:10
Eye muscles
1:1
Recall The Motor Unit:
motor neuron and the muscle fibers it innervates
Spinal
cord The smallest amount of
muscle that can be activated
voluntarily.
Gradation of force in skeletal
muscle is coordinated largely
by the nervous system.
Recruitment of motor units
is the most important means
of controlling muscle tension.
Since all fibers in the motor
unit contract simultaneously,
pressures for gene expression
To increase force: (e.g. frequency of stimulation,
1. Recruit more M.U.s load) are identical in all fibers
2. Increase freq. of a motor unit.
(force frequency)
Physiological profiles of motor units:
all fibers in a motor unit are of the same fiber type

Slow motor units contain slow fibers:

Myosin with long cycle time and therefore uses
ATP at a slow rate.
Many mitochondria, so large capacity to
replenish ATP.
Economical maintenance of force during
isometric contractions and efficient performance
of repetitive slow isotonic contractions.

Fast motor units contain fast fibers:

Myosin with rapid cycling rates.
For higher power or when isometric force
produced by slow motor units is insufficient.
Type 2A fibers are fast and adapted for
producing sustained power.
Type 2X fibers are faster, but non-oxidative
and fatigue rapidly.
2X/2D not 2B.

Modified from Burke and Tsairis, Ann NY Acad Sci 228:145-159, 1974
Increased use: strength training
Early gains in strength appear to be predominantly due to neural
factorsoptimizing recruitment patterns.

Long term gains almost solely the result of hypertrophy i.e.

increased size.
The PI(3)K/Akt(PKB)/mTOR pathway is a
crucial regulator of skeletal muscle Application of IGF-I to C2C12
myotube cultures induced both
hypertrophy/atrophy. increased width and phosphor-
ylation of downstream targets of
Akt (p70S6 kinase, p70S6K;
PHAS-1/4E-BP1; GSK3) but did
NOT activate the calcineurin
pathway.

Treatment with rapamycin

almost completely prevented
increase in width of C2C12
myotubes.

Treatment with cyclosporin or

FK506 does not prevent myotube
growth in vitro or compensatory
hypertrophy in vivo

Recovery of muscle weight

after following reloading is
blocked by rapamycin but not
cyclosporin.

Rommel et al. (2001) Nature Cell Biology 3, 1009.

Performance Declines with Aging
--despite maintenance of physical activity
Performance (% of peak)
100

80

60

40
Shotput/Discus
Marathon
20
Basketball (rebounds/game)

0
10 20 30 40 50 60
Age (years)

D.H. Moore (1975) Nature 253:264-265.

NBA Register, 1992-1993 Edition
Number of motor units declines during aging
- extensor digitorum brevis muscle of humans
AGE-ASSOCIATED
ATROPHY DUE TO BOTH

Individual fiber atrophy

(which may be at least
partially preventable and
reversible through exercise).

Loss of fibers
(which as yet appears
irreversible).

Campbell et al., (1973) J Neurol Neurosurg Psych 36:74-182.

Motor unit remodeling with aging
Central Muscle
nervous
system

Motor

AGING
neuron
loss

Fewer motor units

More fibers/motor unit
Mean Motor Unit Forces:
FF motor units get smaller in old age and decrease in number
S motor units get bigger with no change in number
Decreased rate of force generation and POWER!!
225
200
Maximum Isometric Force (mN)

175 Adult
150 Old
125
100
75
50
25
0
FF FI FR S Kadhiresan et al., (1996)
Motor Unit Classification J Physiol 493:543-552.
Muscle injury may play a role in the development of
atrophy with aging.

Muscles in old animals are more susceptible to contraction-

induced injury than those in young or adult animals.

Muscles in old animals show delayed and impaired recovery

following contraction-induced injury.

Following severe injury, muscles in old animals display

prolonged, possibly irreversible, structural and functional
deficits.
 Disorders of Muscle Tissue
Muscle tissues experience few disorders
Heart muscle is the exception
Skeletal muscle remarkably resistant to
infection
Smooth muscle problems stem from external
irritants
 Disorders of Muscle Tissue
Muscular dystrophy a group of inherited
muscle destroying disease
Affected muscles enlarge with fat and
connective tissue
Muscles degenerate
Types of muscular dystrophy
Duchenne muscular dystrophy
Myotonic dystrophy
 Disorders of Muscle Tissue
Myofascial pain syndrome pain is caused
by tightened bands of muscle fibers
Fibromyalgia a mysterious chronic-pain
syndrome
Affects mostly women
Symptoms fatigue, sleep abnormalities,
severe musculoskeletal pain, and headache
Muscular Dystrophy:
A frequently fatal disease of muscle deterioration
Muscular dystrophies have in the past been classified based on subjective and sometimes
subtle differences in clinical presentation, such as age of onset, involvement of particular
muscles, rate of progression of pathology, mode of inheritance.
Since the discovery of dystrophin, numerous genetic disease loci have been linked to protein
products and to cellular phenotypes, generating models for studying the pathogenesis of the
dystrophies.
Proteins localized in the nucleus, cytosol, cytoskeleton, sarcolemma, and ECM.

Cohn and Campbell (2000) Muscle Nerve 23:1459-1471.

Dystrophin function:
transmission of force to extracellular matrix

DGC
dystrophin
dystroglycan (a and b)
sarcoglycans (a, b, g, d)
syntrophins (a, b1)
dystrobrevins (a, b)
sarcospan
laminin-a2 (merosin)

(Some components of
the dystrophin glycoprotein
complex are relatively
recent discoveries, so one
cannot assume that all
players are yet known.)

Cohn and Campbell (2000) Muscle Nerve 23:1459-1471.

Oxidative and Glycolytic Fibers
ATP
 Creatine
Molecule capable of storing ATP energy

Creatine + ATP Creatine phosphate + ADP

 Creatine Phosphate
Molecule with stored ATP energy

Creatine phosphate + ADP Creatine + ATP

 Muscle Fatigue
Lack of oxygen causes ATP deficit
Lactic acid builds up from anaerobic
respiration
Muscle Fatigue
 Muscle Atrophy
Weakening and shrinking of a muscle
May be caused
Immobilization
Loss of neural stimulation
 Muscle Hypertrophy
Enlargement of a muscle
More capillaries
More mitochondria
Caused by
Strenuous exercise
Steroid hormones
 Steroid Hormones
Stimulate muscle growth and hypertrophy
 Muscle Tonus
Tightness of a muscle
Some fibers always contracted
 Tetany
Sustained contraction of a muscle
Result of a rapid succession of nerve
impulses
Tetanus
 Refractory Period
Brief period of time in which muscle cells
will not respond to a stimulus
Refractory
 Refractory Periods

Skeletal Muscle Cardiac Muscle

 Isometric Contraction
Produces no movement
Used in
Standing
Sitting
Posture
 Isotonic Contraction
Produces movement
Used in
Walking
Moving any part of the body
Muscle Spindle
Muscle Spindle Responses
Alpha / Gamma Coactivation
Golgi Tendon Organs
 Developmental Aspects:
Regeneration
Cardiac and skeletal muscle become amitotic, but can
lengthen and thicken
Myoblast-like satellite cells show very limited regenerative
ability
Cardiac cells lack satellite cells
Smooth muscle has good regenerative ability
There is a biological basis for greater strength in men than
in women
Womens skeletal muscle makes up 36% of their body
mass
Mens skeletal muscle makes up 42% of their body mass
 Developmental Aspects:
Male and Female
These differences are due primarily to the
male sex hormone testosterone
With more muscle mass, men are generally
stronger than women
Body strength per unit muscle mass,
however, is the same in both sexes
 Developmental Aspects: Age
Related
With age, connective tissue increases and muscle
fibers decrease
Muscles become stringier and more sinewy
By age 80, 50% of muscle mass is lost
(sarcopenia)
Decreased density of capillaries in muscle
Reduced stamina
Increased recovery time
Regular exercise reverses sarcopenia