Protein's key role in muscle regeneration unveiled

Drs. Sarvjeet Singh, Pradeep Mammen, and Beverly A. Rothermel
UT Southwestern researchers, including (l-r) Drs. Sarvjeet Singh, Pradeep Mammen, and Beverly A. Rothermel, have demonstrated that cytoglobin plays a crucial role in muscle regeneration after injury.

By Lisa Warshaw

With an enhanced understanding of cytoglobin, researchers have uncovered the inner workings of a protein that serves a vital role in muscle regeneration following injury.

Mammalian skeletal muscle is a dynamic and adaptable tissue, capable of responding to physiological demands and pathophysiological stresses. The initial response to those conditions relies heavily on the muscle’s ability to activate myogenic progenitor cells (MPCs), resulting in the formation of new muscle (myogenesis).

In the latest study, published in the December issue of the Proceedings of the National Academy of Sciences, Dr. Pradeep Mammen, Associate Professor of Internal Medicine at UT Southwestern Medical Center, shows that cytoglobin plays a crucial role in muscle regeneration.

“We demonstrated that cytoglobin, a stress-responsive hemoprotein abundantly expressed in MPCs, is capable of controlling their ability to proliferate, as well as differentiate into new muscle cells,” said Dr. Mammen, who leads the Neuromuscular Cardiomyopathy Clinic at UT Southwestern.

Mammalian skeletal muscle plays a central role in enabling limbs to engage in a variety of daily functions, including the ability to carry objects and to move; however, routine demands of daily use, or exposure to genetic or pathophysiological stressors, can injure muscles. Skeletal muscle has the ability to recover by activating MPCs to generate new muscle fibers in order to restore muscle function and strength.

“We now understand that if MPCs lack cytoglobin, then these muscle-specific stem cells are not able to regenerate new muscle cells following stress and ultimately die,” Dr. Mammen said.

The findings demonstrate that following injury, MPCs are activated and cytoglobin moves into the nucleus, the command center of individual cells. Once in the nucleus, through an as-yet undefined mechanism, cytoglobin regulates the ability of an MPC to both survive the stressor and divide and form new muscle cells.

The study’s implications are potentially significant, noted Dr. Mammen. If researchers can develop a therapeutic approach to increase the amount of cytoglobin selectively within muscle stem cells following an injury, for example, then the cytoglobin may be able to improve skeletal muscle strength and function.

“With an increased understanding of cytoglobin’s role in muscle regeneration, we may be able to develop new therapeutic approaches to treat patients with various neuromuscular disorders, such as Duchenne muscular dystrophy, or those with significant muscle trauma or injury,” Dr. Mammen said.

Others involved in the investigation included first author Dr. Sarvjeet Singh, Assistant Instructor of Internal Medicine, and co-corresponding author Dr. Beverly A. Rothermel, Associate Professor of Internal Medicine and Molecular Biology.

Future research will attempt to isolate the mechanism by which cytoglobin controls the fate of muscle-specific stem cells. Additionally, Dr. Mammen plans to apply these findings to various neuromuscular disorders in an effort to learn how to rescue muscles from genetic injuries.

Funding was provided by the American Heart Association, the Donald W. Reynolds Foundation, the GlaxoSmithKline Research Foundation, and the National Institutes of Health.