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Skeletal Muscle Physiology
Susan V. Brooks Herzog
Department of Physiology
University of Michigan
Structural hierarchy of skeletal muscle
Muscle
Muscle fibers
Muscle fiber
Sarcomere
A little less than half of the body’s
mass is composed of skeletal
muscle, with most muscles linked
to bones by tendons through which
the forces and movements
developed during contractions
are transmitted to the skeleton.
Myofibril
Modified from McMahon, Muscles, Reflexes and Locomotion
Princeton University Press, 1984.
Sarcomere: functional unit of striated muscle
Modified from Vander, Sherman, Luciano
Human Physiology, McGraw-Hill.
Cross-sectional views of:
Myosin filaments
thin filament
lattice
overlap
region
center of
sarcomere
thick filament
lattice
Z line
Actin filaments
Actin filaments
Electron
micrograph
1 mm
I band
A band
Sarcomere
I band
Myosin is a molecular motor
2 nm
Modified from Vander, Sherman, Luciano
Human Physiology, McGraw-Hill.
Coiled coil of two a helices
Myosin is a hexamer:
2 myosin heavy chains
4 myosin light chains
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.
Hypothetical model of the
swinging lever arm
Working stroke produced by
opening and closing of the
nucleotide binding site, resulting
in rotation of the regulatory
domain (neck) about a fulcrum
(converter domain).
Sub-nanometer rearrangements at
active site are geared up to give 510 nm displacement at the end of
the lever arm.
Ruegg et al., (2002) News Physiol Sci 17:213-218.
How striated muscle works: The Sliding Filament Model
From Vander, Sherman, Luciano
Human Physiology, McGraw-Hill.
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.
Chemomechanical coupling – conversion of chemical energy
(ATP about 7 kcal/mole) 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 dependent 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:
Biceps muscle shortens
during contraction
• shortening
(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
Modified from Vander, Sherman, Luciano
Human Physiology, McGraw-Hill.
Motor Units: 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.
Modified from Vander, Sherman, Luciano
Human Physiology, McGraw-Hill.
• 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.
From Matthews GG Cellular Physiology of Nerve and Muscle Blackwell Scientific Publications.
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.
Muscle is plastic!
Muscle “adapts” to meet the habitual level of demand placed on it, i.e. level of
physical activity.
Continuum of Physical Activity
Level of physical activity
determined by the
frequency of recruitment and the load.
Decrease muscle use
– prolonged bed rest
– limb casting
– denervation
– space flight.
endurance
trained
Load
Increase muscle use
– endurance training
– strength training
(cannot be optimally
trained for both strength
and endurance)
strength
trained
controls
inactivity
Frequency of recruitment
Adapted from Faulkner, Green and White
In: Physical Activity, Fitness, and Health, Ed. Bouchard, Shephard and Stephens
Human Kinetics Publishers, 1994
Endurance training
Little hypertrophy but major biochemical adaptations within muscle fibers.
Increased numbers of mitochondria; concentration and activities of oxidative
enzymes (e.g. succinate dehydrogenase, see below).
Succinate dehydrogenase (SDH)
activity:
Low activity light
High activity dark
Control
Images courtesy of John Faulkner and Timothy White
12-weeks
treadmill running
A calcineurin dependent transcriptional • Calcineurin is a Ca2+-regulated
serine/threonine phosphatase.
pathway appears to control skeletal
• Caclineurin dephosphorylates
muscle fiber type.
nuclear factor of activated T cells
(NFAT) transcription factors.
• Dephosphorylated NFATs
translocate to the nucleus where
combinatorially with other factors
they activate transcription.
•
A second target of calcineurin is
the transcriptional co-activator,
peroxisome-proliferator-activated
receptor-g co-activator-1 (PGC1a).
•
Activation of calcineurin in
skeletal myocytes selectively upregulates slow-fiber-specific gene
promoters and the effect enhanced
with PGC-1a expression
•
Lin et al. (2002) Nature 418:797-801
PGC-1a activates mitochondrial
biogenesis.
A calcineurin dependent transcriptional
pathway appears to control skeletal
muscle fiber type.
•
Cyclosporin is widely used
clinically to prevent rejection of
transplanted tissues; patients
develop skeletal muscle
myopathy and loss of oxidative
capacity.
• Cyclosporin (and FK-506) are
specific inhibitors of calcineurin
and thereby block T cell
activation.
• Cyclosporin administration to
intact animals promotes slowto-fast fiber transformation.
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.
Disuse causes atrophy -- USE IT OR LOSE IT!
Individual fiber atrophy (loss of myofibrils) with no loss in fibers.
Effect more pronounced in Type II fibers.
“Completely reversible” (in young healthy individuals).
ATPase activity:
Type I fibers light
Type II fibers dark
Control
Prolonged
bed rest
Images courtesy of John Faulkner
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 human beings
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
•
•
Fewer motor units
More fibers/motor unit
AGING
Motor
neuron
loss
Muscle
Maximum Isometric Force (mN)
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
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.
Injured fibers (% total)
Only lengthening contractions result in damaged fibers
20
15
control
passive
isometric
lengthening
different from
* zero
(p<0.05)
*
10
5
0
Other Measures of Contraction-Induced Injury
immediate mechanical disruption observed by EM.
enzyme release from degenerating muscle fibers
in human beings, subjective reports of muscle soreness
in the absence of fatigue, a decrease in the development
Koh & Brooks (2001)
of force
Am J Physiol 281:R155-R161.
“Ghost” fiber 3 days after initial injury
Faulkner, Brooks and Zerba (1995)
J Gerontol 50:B124-B129.
Repair through activation of satellite cells
Perry and Rudnicki (2000)
Frontiers in Bioscience 5:D750-67.
4 days after damage
2 weeks after damage
4 weeks after damage
with irradiation
Myology (Sanes, McGraw-Hill, 1994)
A single prior exposure to a protocol of lengthening
contractions reduced the force deficit and damaged fibers
60%
non-trained
50
2 weeks post
40
30
20
* p < 0.05
*
10
0
Koh & Brooks (2001)
Am J Physiol 281:R155-R161.
*
Force Deficit
(% control)
Injured Fibers
(% total)
60
50
40
* *
*
non-trained
trained passive
trained isometric
different from non-trained (p<0.05)
60
50
40
30
30
20
20
*
10
0
Force deficit
Injured fibers
10
0
Injured fibers (% total)
Force deficit (% control)
Degeneration-regeneration not necessary to provide muscles
protection from contraction-induced injury
Koh & Brooks (2001)
Am J Physiol 281:R155-R161.
•
Despite the increase in susceptibility to injury with aging,
and the decreased ability to recover, muscles in old
animals can be conditioned for protection from injury.
•
Maintenance of conditioned fibers, particularly in muscles
of elderly people, may prevent inadvertent damage during
contractions.
Microstructure
Modified from Squire, Muscle: Design, Diversity, and Disease
Benjamin/Cummings, 1986
Originally from Lazarides (1980) Nature 283:249-256.
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.