Model: skeletal neuromuscular junction
- striated skeletal muscle cell pic* pic
- innervated muscle fiber* pic & neuromuscular junction*

Muscles can not push, they may only only CONTRACT (pull)
A muscle contraction is called a muscle TWITCH
4 parts of a Muscle twitch [ CONTRACTION CYCLE *]
1) latent period - 5 msec time between application of AP & initiation of contraction
2) contraction - 40 msec muscle shortens & does its work
3) relaxation - 50 msec muscle elongates & returns to original position
4) refractory period - 2 msec time of recovery between stimulations of muscle

some definitions related to muscle contraction...
Summation - a 2nd contraction before 1st subsides fig* (cause is time differential of nerve/muscle)
Tetany - sustained contractions (requires energy - ATP) - Harvey Project - muscle twitch
Fatigue - under repeat stimulation, contractions get feebler, lactate accumulates,
pH changes lead to stoppage of contractions
Shivers - involuntary-summed muscle contractions which release waste heat, that warms body

Major muscle TYPES...
Myosins are protein motors. Upon interaction with actin filaments, they utilize energy from
ATP hydrolysis to generate mechanical force.
Muscles are typed based upon the types of myosin protein fibers present
(also called heavy meroyosins*):

there are different isoforms (structure versions) of the muscle myosins -
TYPE I (Slow Twitch) & Type IIa/IIx (Fast Twitch)


2 TYPES of MUSCLE FIBERS... determined both genetically & functionally
based upon how fast they can produce a contractile twitch
every muscle composed of varying % composition of two types
Tonic muscles (red) - Leg muscles TYPE II - (IIa & IIx) FAST TWITCH
Tetanic muscles (white) - Pectoral muscles
slower contraction times (110 msec) faster contraction times (50 msec)
contain myoglobin (red) no myoglobin (white)
continuous use muscles - prolonged performance
for endurance performance ( marathoners) one time use muscles - brief performances
for power & speed (sprinters)
marathoner: 80% type I & 20% type II sprinter: 20% type I & 80% type II
Distribution of Slow & Fast Twitch muscle in Humans* down
best in long slow sustained contractions best in rapid (short) contractions
not easily fatigued easily fatigued
more capillary beds, greater VO2 max less capillary beds
smaller in size larger in size
lower glycogen content higher glycogen content
poor anaerobic glycolysis * predominantly anaerobic glycolysis
easily converts glycogen to lactate wo O2
* predominant aerobic enzymes & metabolism some aerobic capacity
higher fat content lower fat content
more mitochondria - Beta Oxidation high fewer mitochondria- Beta Oxidation low
poorly formed sarcoplasmic reticulum well formed sacroplasmic reticulum
slower release of Ca = slower contractions quick release of Ca = rapid contractions
tropinin has lower affinity for Ca troponin - higher affinity for Ca

Relative Distributions of Slow Twitch & Fact Twitch Myosin Isoforms (Type I & Type II)
Type I (slow) Type II (fast) Type IIa Type IIx
Average person 50% 50% 40% 10%
spinal injury 4% 96% 48% 48%
sprinter 20% 80% 45% 35%
couch potato 40% 60% 30% 30%
marathoner 80% 20% 20% 0%
These myosin isoforms are conserved evolutionarily:
Comparing myosin isoforms from different mammals reveals remarkably little variation species to species. Rat type I is more similar to human type I myosins, than it is to rat type II's. Thus selective evolution has maintained a functional difference between type I's & type II's over eons of evolution.

Model: Vertebrate Skeletal Muscle - multinucleate cell* - muscle to myofibril*

SARCOMERE - basic repeat unit of striated muscle, delimited by Z-lines
I band - "clear zone" around Z-line (Isotropic - passes light in all directions)
A band - "dark region" in center of sarcomere (Anisotropic - in different directions)
M line - mid point of the sarcomere
H zone - "clear zone" in the center of sarcomere around M line

SLIDING FILAMENT THEORY of Muscle Contraction (Hugh Huxley)
A band remains constant in its size dimensions
H Zone becomes denser contraction**
I band varies in length becoming shorter & disapperaring
relaxed/contracted at molecular level* actin/myosin*

contraction animation*

Muscle Cell Proteins [4 types involved in contraction cycle]

myosin* - 2 polypeptides twist to form helix with globular end,
which has ATPase activity & an affinity to bind to actin
myosins are... Molecular Motors* kinesin animations

G-actin* - globular protein which polymerizes into polymeric fiber
contains a myosin binding site

3. Tropomyosin* - fiber-like protein which wraps helically around thin filament

4. Troponin* - globular protein complex which binds Ca+2 & initiates contraction cycle
is a complex of 3 proteins, Troponins C, I, & T, which bind Ca; Troponin C (18 kD) binds Ca reversibly.
TnC binds TnI (23 kD) & TnT (37 kD), which change conformation in response to TC binding Ca, but not actin.

Muscle Contraction Cycle, Sarcoplasmic Reticulum, & Role of Ca ...

1. muscle - sarcoplasmic reticulum (ER)*
2. T-tubes conduct impulses* Animations
3. Ca release at T-tubes** a. Brooks & Cole muscle Structure
4. troponin binds Ca & opens myosin sites* b. Harvey Project junction animation
5. actin+myosin* & ATP contraction cycle* b. Harvey Project - Sliding Lever Arm
6. REVIEW cycle - web muscle movie** d. K.C. Holmes, Max Planck Inst. - ATP
7. Complete cycle: Blackwell Pub.**

Steroids* & Doping and Muscle Cell Growth*

The Performance Enhancing Drugs of the Future...

not steroids, but the introduction of artificial genes: Figure*

1. genes for myosin type transcriptions factors, that will activates genes
genes for long dormant myosin isoforms of our ancient ancestors...
say an ancient type IIb isoform
that's faster than any known Type II isoform of today

2. or IGF-I* (insulin-like growth factor)
IGF-I is a growth factor structurally related to insulin and IGF-I is produced in
response to GH and then induces subsequent cellular activities, particularly on bone growth. IGF-I
has autocrine and paracrine activities, and like the insulin receptor, it has intrinsic tyrosine kinase
activity. Owing to their structural similarities IGF-I can bind to the insulin receptor.

Muscle Cell Growth includes:
1. satellite cell recruitment*, which proliferate & fuse with muscle cell fibers
2. pro-growth factors as IGF-I, which promotes satellite cell proliferations
3. growth inhibition factors, such as myostatin

Current research - H.L. Sweeney at U. Penn
have used adeno-associated virals (AAV) to infuse IGF-I gene* into recipient muscle cells

in normal mice: experiments have overall size & growth rates up 15% to 30%
in mice genetically engineered to overproduce IGF-I: seen 20% to 30% larger muscle mass
overproduction also hastens muscle repair in mice with M.D.
injection of AAV-IFG-I into one leg of lab rats with an 8 week weight training program
= 2x increase in strength in treated leg
= longer period before gained strength is lost
= sedentary rats showed 15% increased strength

Human trials for IFG-I injections to treat myotonic (prolonged contraction) dystrophy
are set to begin next year...
next to be followed by athletic gene doping?

Myostatin... is a muscle inhibitory growth factor [blocks muscle growth],
it promotes atrophy and slow muscle cell growth,
may function antagonistically with IGF-I, which promotes muscle growth.
discovered by Se-jin Lee at Johns Hopkins in 1997
defective myostatin genes = considerably larger muscle mass
Belgian Blue cattle* and a human case study* -->
the Breed & its cause reference
may be useful in muscle debilitating diseases, which include:
muscular dystrophy -
sarcopenia - age realted muscle loss
cachexia - aggressive muscle loss in cancer & HIV patients
myoclonus - abnormal muscle contractions

Wyeth pharmaceuticals is at work on myostatin inhibitors
1st drugs to date are antibodies to myostatin and
some clinical trials are set to begin in M.D. patients
end Training, Muscle Fiber Recruitment, & Performance & Marathoner

Muscle Performance, Training, & Fiber Recruitment

Disuse of a muscle, as in space travel (weightlessness),
or a couch potato can shrink a muscle by 20% in 2 weeks.

Weight Training can increase muscle mass to 150% of normal size.

How do muscles get bigger and better?

by making more muscle proteins... nuclei of muscle control translation,
thus one needs more nuclei, but muscle cell nuclei don't divide.
New nuclei come from independent adjacent cells (Satellite stem cells*).

when muscles under rigorous exercise they "tear", and the damaged area
attracts satellite cells into the tears, depositing more nuclei.
weight training thus leads to heterotrophy of muscles......
more nuclei equals muscle enlargement due to more protein synthesis.

Recruitment of Muscle Fibers (Slow <---> Fast) Is it Possible ?
has implications for spinal injury & athletics

1. Cross innervation: experimentally switch nerve innervations (slow to fast)
animal experiments have lead to some conversions

2. Spinal injury: a lack of nerve impulse & muscle atrophy leads to a sharp
decrease of the slow myosin isoform (type I),
while the amount of the fast isofrom increases (type II) table*

Conclusion: neural input (electrical stimulation) is necessary for the
proper genetic expression of the Slow - Type I isoform.
Electrical stimulation can reintroduce the slow fiber into
paralyzed muscles.


3. Weight Training and Different Myosin Types
sedentary people have higher amounts of IIx
active people have more IIa fibers

heavy weight-load repetitions.....
decreases Fast IIx fibers and converts them to Fast IIa fibers
nuclei stop expressing IIx gene and express IIa genes
after 1 month all IIx --> IIa (muscle also become more massive)

4. Tapering - can we change amounts of IIx fibers?
in experiments involving sedentary young adults:
heavy resistance training (3 months) reduced IIx from 9% to 2%
but, a taper (rest for 3 months) & IIx returned above basline (9%)
to a level of 18%, i.e., more fastest twitch fibers. fig

5. Can we recruit slow ---> fast ? maybe...
but no good evidence to date for slow to fast recruitments.

a protein called PPAR-delta, discovered by Ron Evans of Salk Institute
regulates other genes involved in fat metabolism.
High activity of PPAR-d burns more fat, results in leaner, more fit individuals.

recent experiments (PLoS - Oct 2004)
revealed that mice genetically modified to produce more PPAR-d
- had 2x more slow twitch (I) muscle compared to litter-mates. [fig]*
- PPAR-d mice could run 1,800m (2x normals) before reaching exhaustion.

these changes are similar to those induced by sustained training & exercise
long lasting vigorous exercise produces a higher ratio od slow twitch (I) muscle.

a new drug (GW501516) activates PPAR-d directly leading to similar changes
- could help obese and heart disease patients who can't exercise.
GlaxoSmithKline is currently testing this drug in obese, diabetics

Articolo redatto dall'Università di Miami, dipartimento di Biologia.