IGF-1 Most Powerful Mediators of Muscle Growth

Summary:

Although the mechanisms underlying age associated muscle
loss are not entirely understood, researchers attempted to moderate the loss by
increasing the regenerative capacity of muscle. This involved the injection of
a recombinant adeno-associated virus directing overexpression of insulin-like
growth factor I (IGF-I) in differentiated muscle fibers.

They demonstrated that the IGF-I expression promotes an
average increase of 15% in muscle mass and a 14% increase in strength in young
adult mice (Figure 1), and remarkably, prevents aging-related muscle changes in
old adult mice, resulting in a 27% increase in strength as compared with
uninjected old muscles (Figure 2). Muscle mass and fiber type distributions
were maintained at levels similar to those in young adults. These results
suggest that gene transfer of IGF-I into muscle could form the basis of a human
gene therapy for preventing the loss of muscle function associated with aging
and may be of benefit in diseases where the rate of damage to skeletal muscle
is accelerated.

Discussion:

I’m not sure where to begin. This study has the potential
to completely change the way we age.

In this experiment, a recombinant adeno-associated virus,
directing overexpression of insulin-like growth factor I (IGF-I) in mature
muscle fibers, was injected into the muscles of mice. The DNA that was
originally in the virus was removed along with markers that stimulate immune
response. DNA coding for IGF-1 was then put into the virus along with a
promoter gene to ensure high rates of transcription. The results, as you can
see by figures 1 & 2, were dramatic.

IGF-1 plays a crucial role in muscle regeneration. IGF-1
stimulates both proliferation and differentiation of stem cells in an
autocrine-paracrine manner, although it induces differentiation to a much
greater degree. IGF-1, when injected locally, increases satellite cell
activity, muscle DNA, muscle protein content, muscle weight and muscle cross
sectional area. The importance of IGF-1 lies in the fact that all of its
apparent functions act to induce muscle growth with or without overload
although it really shines as a growth promoter when combined with physical
loading of the muscle.

IGF-1 also acts as an endocrine growth factor having an
anabolic effect on distant tissues once released into the blood stream by the
liver. IGF-1 possesses the insulin-like property of inhibiting degradation, but
in addition can stimulate protein synthesis. The insulin-like effects are
probably due to the similarity of the signaling pathways between insulin and
IGF-1 following ligand binding at the receptors.

The ability of IGF-I to stimulate protein synthesis
resembles the action of GH, which was shown in separate studies on volunteers
to stimulate protein synthesis without affecting protein degradation. Although
it is often believed that the effects of GH are mediated through IGF-1, this
cannot be the case entirely. First, the effects of the two hormones are
different, in that GH does not change protein degradation. Second, the effect
of GH is observed with little or no change in systemic IGF-1 concentrations.
Age related muscle loss has been prevented with GH injections, however it is
believed that this is accomplished through IGF-1.

The results of this study are similar to other studies
where IGF-1 was injected directly into muscle tissue, resulting in increases in
size and strength of experimental animals. Using a virus as a genetic vehicle
has an advantage over simply injecting the growth factor. The effects of a
single viral treatment last significantly longer (months if not years) because
the muscle cell itself is constantly overproducing its own IGF-1 from injected
DNA.

The fact that the IGF-1 produced by the muscle of these
mice did not reach the blood stream is interesting. Systemic injections of
IGF-1 have not been successful in inducing this kind of anabolic effect in
humans. In addition, IGF-1 produced by the liver is genetically different than
that produced by muscle tissue. It could be that providing additional DNA for
the muscle to produce it’s own IGF-1 is the key to achieving anabolic and
rejuvenative effects specifically in skeletal muscle.

In this study there was a preferential preservation of
type IIb muscle fibers in aging mice. These are the fibers most sensitive to
muscle hypertrophy from training and they are also the first fibers to
disappear with aging. In the mice receiving the engineered virus, there was
also a preservation of the motor neuron, leading to an increase in functional
capacity. It is speculated that age related muscle loss is secondary to the
loss of neuronal activation of type-II fibers. By preventing the degeneration
of typ-II motor units, functional capacity could be maintained into old age.
This technique may also serve useful in the prevention of osteoporosis. Further
study is necessary to determine wether IGF-1 is having an effect only on muscle
fibers or on nervous tissues as well.

Finally, it was also exciting to see muscle growth in the
young mice who received the injection (15% increase in muscle mass). This means
that the injection provided levels of IGF-1 far and above what the muscle
normally has access to and not simply a preservation of normal levels. Remember
that this was not combined with exercise. The growth of the injected muscles
happened even without an extreme mechanical stimulus. The mice were simply
allowed to run around as they usually do. Because of these dramatic results,
the authors expressed concern about the use of this technique to enhance
performance or cosmetic appearance. Research Update is not my personal soap box
so I won’t go off on the gender centered hypocrisy of cosmetic enhancement in
our society. All we can hope for is that this technique will be used to treat
more important diseases such as muscular dystrophy and thereby become somewhat
available for other uses as well.

Researchers:

Elisabeth R. Barton-Davis*, Daria I. Shoturma*, Antonio
Musaro, Nadia Rosenthal, and H. Lee Sweeney*,

* Department of Physiology, University of Pennsylvania
School of Medicine, Philadelphia, PA and Cardiovascular Research Center,
Massachusetts General Hospital, Charlestown, MA

Source:

Proc Natl Acad Sci U S A 1998 Dec 22;95(26):15603-7


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