Possible muscle disease therapeutic target found

Their work is published the week of August 6 by Proceedings of the National Academy of Sciences.

Myostatin is known to inhibit muscle growth and its function is common in many mammals, including cows, sheep, dogs, humans, and mice. Mutant mice lacking in myostatin have muscle mass that is almost double that of normal mice. This property is what makes it an attractive potential drug target. By inhibiting myostatin a drug could, in theory, promote muscle growth, even in a person with a muscular disease.

There has been considerable debate about which types of muscle cells are targeted by myostatin: fibrous muscle cells called myofibers, or muscle stem cells called satellite cells. The satellite cells are activated by muscular injury, begin to divide, and fuse to myofibers. Some studies seem to indicate myostatin targets satellite cells, others indicate myofibers.

The research team, co-led by Fan and Se-Jin Lee, who is a former Carnegie Staff Associate and currently at Johns Hopkins University Medical School, used a variety of techniques -- both genetic and pharmacological -- and determined that the muscle growth caused by inhibiting myostatin does not significantly involve the incorporation of satellite cells into myofibers.

This finding has major implications for the possible use of myostatin as a clinical target. There are outstanding questions about how a drug designed to target myostatin would work in clinical conditions in which patient's satellite cells are depleted. For example, in diseases like muscular dystrophy, satellite cells are believed to compensate for degenerated muscle cells in the early stages of the disease, causing the pool of these stem cells to shrink over time. This work raises the possibility that these patients might still benefit from myostatin inhibitors.

"More work is needed to determine whether these findings are applicable to various clinical conditions, such as exercise, injury, and sarcopenia -- degenerative loss of muscle mass associated with aging," Fan said. "However, our findings initially indicate that many different diseases affecting the muscular system could potentially be responsive to drugs that inhibit myostatin and thus promote muscle growth, without regard to the status of the muscle stem cell pool."

The other co-authors on the study are Than Huynh, Yun-Sil Lee, and Suzanne Sebald of the Johns Hopkins University School of Medicine; Sarah Wilcox-Adelman of the Boston Biomedical Research Institute; Naoki Iwamori and Martin Matzuk of Baylor College of Medicine.