Skeletal Muscle Physiology

Susan V. Brooks Herzog

Department of Physiology
University of Michigan
 Structural hierarchy of skeletal muscle

Muscle

A little less than half of the body’s

mass is composed of skeletal
muscle, with most muscles linked
Muscle fibers to bones by tendons through which
the forces and movements
developed during contractions
Muscle fiber
are transmitted to the skeleton.

Myofibril
Sarcomere

Modified from McMahon, Muscles, Reflexes and Locomotion

Princeton University Press, 1984.
 Sarcomere: functional unit of striated muscle

Modified from Vander, Sherman, Luciano

Cross-sectional views of:
Human Physiology, McGraw-Hill.

Myosin filaments

Z line Actin filaments Actin filaments

thin filament overlap center of thick filament
lattice region sarcomere lattice

Electron
micrograph
1µ m

I band A band I band

Sarcomere
 Myosin is a molecular motor Myosin is a hexamer:
2 myosin heavy chains
Modified from Vander, Sherman, Luciano
4 myosin light chains
Human Physiology, McGraw-Hill.
Coiled coil of two α helices

2 nm
C terminus

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

.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)

News Physiol Sci 17:213-218.
(motor) domain
 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

Power Stroke
(converter domain).

Sub-nanometer rearrangements at
active site are geared up to give 5-
10 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 β 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
(Isotonic: shortening
• shortening
during contraction
against fixed load,
speed dependent on
M·ATPase activity and
load)

• isometric

Most likely to cause

• lengthening Biceps muscle lengthens
during contraction 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
Modified from Vander, Sherman, Luciano
of controlling muscle tension.
Human Physiology, McGraw-Hill.

• 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)
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.

Level of physical activity Continuum of Physical Activity

determined by the
frequency of recruit- strength
trained
ment and the load.

Increase muscle use

– endurance training
– strength training endurance
Load

(cannot be optimally trained

trained for both strength controls
and endurance)

Decrease muscle use

– prolonged bed rest inactivity
– limb casting
– denervation Frequency of recruitment
Adapted from Faulkner, Green and White
– space flight. 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 dehy-
drogenase (SDH)
activity:
Low activity light
High activity dark

Control 12-weeks
treadmill running
Images courtesy of John Faulkner and Timothy White
A calcineurin dependent transcriptional • Calcineurin is a Ca -regulated
pathway appears to control skeletal
muscle fiber type.
Lin et al. (2002) Nature 418:797-801
2+
serine/threonine phosphatase.
• Caclineurin dephosphorylates
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-γ co-activator-1 (PGC-
1α ).
• Activation of calcineurin in
skeletal myocytes selectively up-
regulates slow-fiber-specific gene
promoters and the effect enhanced
with PGC-1α expression
• PGC-1α 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 slow-
to-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 • 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.
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
Performance Declines
Declines with
with Aging
Aging
--despite
--despite maintenance
maintenance of
of physical
physical activity
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 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
Motor unit
unit remodeling
remodeling with
with aging
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
Maximum Isometric Force (mN)

200
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.
 Only lengthening contractions result in damaged fibers
20
control *

Injured fibers (% total)

passive
isometric
lengthening
15
* different from
zero (p<0.05)
10

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
of force Koh & Brooks (2001)
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 * p < 0.05
30
*
20
10
*
0
Koh & Brooks (2001)
Force Deficit Injured Fibers
Am J Physiol 281:R155-R161. (% control) (% total)
Degeneration-regeneration not necessary to provide muscles
protection from contraction-induced injury
Force deficit (% control)

60 non-trained 60

Injured fibers (% total)

trained passive
50 trained isometric 50
40 * * * different from non- 40
-trained (p<0.05)
30 30
20 20
10
* 10
Koh & Brooks (2001)
0 0 Am J Physiol 281:R155-R161.
Force deficit Injured fibers

• 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
ystrophin
ystroglycan (α and β )
arcoglycans (α , β , γ , δ )
yntrophins (α , β 1)
ystrobrevins (α , β )
arcospan
aminin-α 2 (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.