SMA /CMT

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This article is dated 10/26/01

NEW CLUES TO MUSCLE ATROPHY IN ALS, SMA, CMT

Scientists have found two genes whose normal function appears to be to

accelerate muscle atrophy — a process of muscle breakdown that occurs as a

consequence of disuse, injury, aging and certain neuromuscular diseases.

The findings might yield insights into treatments for amyotrophic lateral

sclerosis (ALS), spinal muscular atrophy (SMA) and Charcot-Marie-Tooth disease

(CMT), says Louis M. Kunkel, an MDA grantee and geneticist at Children's

Hospital of Boston.

In ALS and SMA, the death of muscle-controlling nerve cells (motor neurons)

in the spinal cord causes severe atrophy of voluntary muscles throughout the

body. In CMT, damage to the peripheral nerves that carry signals from the spinal

cord to muscles causes a milder atrophy of muscles in the extremities.

In an MDA-funded study, Alfred Goldberg of Harvard Medical School in Boston

induced muscle atrophy in mice by depriving them of food for a brief period.

When he extracted genetic material from their leg muscles, he found a gene that

was turned on above normal levels, which he’s named " atrogin. "

He went on to show that the atrogin boost occurs before the onset of muscle

atrophy, and is common to muscle atrophy in many disease states — for

instance,

diabetes and liver disease. The study has been published online by the

Proceedings of the National Academy of Sciences.

In a study published in the Oct. 26 issue of Science, Sue Bodine and her

colleagues at Regeneron Pharmaceuticals in Tarrytown, N.Y., induced atrophy of a

leg muscle in rats by severing the nerve to the muscle, or by preventing its

use. In each case, they, too, observed an upregulation of atrogin (which they

call MAFbx) — and another gene, MuRF1. Deleting either gene in mice made the

mice resistant to muscle atrophy, and delivering the atrogin gene to muscle

cells

caused the cells to undergo atrophy, they found.

The atrogin and MuRF1 genes both encode " ubiquitin ligases, " a family of

proteins that mark other proteins for destruction. Finding drugs that block the

activity of atrogin or MuRF1 might be an effective way to prevent muscle

atrophy, Goldberg and Bodine suggest.

Kunkel, who's using " gene chip " technology to search for genes that modify

the course of muscular dystrophy, says such drugs " might alleviate some of the

symptoms and make the quality of life better for people with motor neuron

diseases [like ALS and SMA] and peripheral nerve disorders [like CMT]. " However,

it's not yet known whether atrogin and MuRF1 contribute to the muscle atrophy

that occurs in those diseases, he says.