1. health and fitness
2. disease

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
•
Sarcomeres: Z
Disk to Z Disk
Sarcomere - repeating functional units of a
myofibril
– About 10,000 sarcomeres per myofibril,
end to end
– Each is about 2 µm 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
•
Myosin (Thick)
Myofilament
•
•
•
Many elongated myosin molecules shaped
like golf clubs.
Single filament contains roughly 300
myosin molecules
Molecule consists of two heavy myosin
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
3. Troponin
Two strands of fibrous (F) actin form a
double helix extending the length of the
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.
Actin (Thin)
Myofilaments
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
Troponin
Ca2+
Tropomyosin
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 (Cont’d)
• 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 (cont’d)
• 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
2 nm
Coiled coil of two a helices
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
(motor) domain
neck region/lever arm
Ruegg et al., (2002)
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 M·ATPase 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 genes…arranged 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
Mosby—Year Book, Inc., 1993.
Three Potential Actions During Muscle Contraction:
• shortening
Biceps muscle shortens
during contraction
(Isotonic: shortening against fixed
load, speed dependent on
M·ATPase activity and load)
• isometric
• lengthening
Biceps muscle lengthens
during contraction
Most likely to cause
muscle injury
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
To increase force:
1. Recruit more M.U.s
2. Increase freq.
(force –frequency)
unit contract simultaneously,
pressures for gene expression
(e.g. frequency of stimulation,
load) are identical in all fibers
of a motor unit.
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
factors…optimizing 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
hypertrophy/atrophy.
•
Application of IGF-I to C2C12
myotube cultures induced both
increased width and phosphorylation 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 (% of peak)
Performance Declines with Aging
--despite maintenance of physical activity
100
80
60
40
Shotput/Discus
Marathon
Basketball (rebounds/game)
20
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
nervous
system
AGING
Motor
neuron
loss
Muscle
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!!
Maximum Isometric Force (mN)
225
200
Adult
Old
175
150
125
100
75
50
25
0
FF
FI
FR
Motor Unit Classification
S
Kadhiresan et al., (1996)
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 contractioninduced 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
• Women’s skeletal muscle makes up 36% of their body
mass
• Men’s 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