Skeletal muscle wasting is more complex than simply a somewhat haphazard decrease in muscle size, according to a new study by Harvard Medical School scientists. It is a regulated, programmed, biochemical process in which distinct muscle components are broken down in an ordered manner.

The research, supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, indicates that separate destructive processes work to disassemble thick and thin muscle filaments, the protein-composed muscle-cell structures that generate strength by pushing past one another when muscles contract. Muscle wasting with loss of function is a major problem in aged populations, and this new information could be particularly useful to researchers studying muscle loss and trying to develop therapies to combat this debilitating process in an era when the U.S. population is rapidly aging.

Prior research in the Harvard laboratory of Alfred Goldberg, Ph.D., had indicated that during various types of muscle atrophy, a specific set of genes (which they termed "atrogenes") are induced in the muscle and promote the loss of muscle tissue. Shenhav Cohen, Ph.D., Dr. Goldberg and their colleagues began their recent study of the mechanisms of muscle breakdown by concentrating on a gene called MuRF1, which is only active in atrophying muscles. This gene codes for a kind of enzyme that attaches a molecule called ubiquitin to cell proteins, thus tagging them for rapid destruction to their constituent amino acids in a cellular structure termed the proteasome. MuRF1, they showed, is specialized to tag proteins that make up the contractile machinery that determines muscle strength and that are organized as filaments in bundles called myofibrils within muscle cells. The researchers studied mice with normal copies of the gene and others with defective copies. When they subjected both mouse populations to wasting conditions, they discovered that:

  • Mice with the defective genes had less muscle breakdown, and specifically less loss of myofibrils, confirming that MuRF1 is important in destroying filaments.
  • MuRF1 acted directly on intact bundles of filaments. There had been some earlier suggestions that the myofibrils containing the bundles of filaments within the muscle cell had to first be breached by other enzymes to make the filaments ready for breakdown.
  • The breakdown in thick and thin muscle filaments was not uniform. Three minor components of the thick filaments were destroyed early in the process, while the major component (myosin) was modified by MuRF1 later. Perhaps, the researchers speculate, the presence of the first three thick-filament components had been stabilizing the fourth. Components of the thin filaments, however, were destroyed even in mice without MuRF1, showing that a different ubiquitin-tagging enzyme acts on these filaments.

Their work, the scientists say, shows that the filament breakdown mechanism is not sudden, but orderly and gradual, allowing muscle cells to keep functioning--although at a reduced capacity--as the wasting process proceeds. Based on these new findings, the researchers conclude that it may not be wise to try stopping or even reversing the destruction process by concentrating on the MuRF1/ubiquitin mechanism, since this ubiquitin-dependent enzyme breaks down only some components of the muscle.

The study, published in the June issue of the Journal of Cell Biology, was also supported by grants from the Muscular Dystrophy Association and the Ellison Medical Foundation and a scholarship to Dr. Cohen from the International Sephardic Education Foundation. Harvard investigators were joined in their work by colleagues from Regeneron Pharmacueticals and the Novartis Institutes for Biomedical Research.

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Cohen, S., et. al. During muscle atrophy, thick, but not thin, filament components are degraded by MuRF1-dependent ubiquitylation. J. Cell Biol. 2009; 185(6):1083-1095.

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