Myostatin (MSTN) is a secreted protein that normally acts to suppress muscle growth. Mice genetically engineered to lack MSTN activity have dramatic increases in muscle mass as a result of a combination of muscle fiber hypertrophy and increased fiber numbers. Moreover, administration of a number of different MSTN inhibitors to wild type mice can also promote muscle growth, demonstrating that MSTN plays a critical role in regulating muscle growth in adult animals. As a result, there has been considerable interest in the possibility that inhibitors of MSTN signaling might be effective in enhancing muscle strength and regeneration in patients with muscle wasting. Although most of the focus on MSTN inhibitors as potential therapeutic agents has focused on their ability to promote muscle growth, several studies have demonstrated that loss of MSTN signaling leads to significant reductions in levels of fibrosis in mouse models of muscular dystrophy. Whether these reductions in fibrosis result indirectly from the anabolic effects of MSTN loss or whether MSTN signals directly to fibroblasts to regulate fibrosis in vivo is not known. The overall aims of this project are to elucidate the mechanisms by which MSTN regulates fibrosis in vivo and to identify the most optimal strategies for exploiting this signaling pathway for the development of new therapies to prevent or reverse the development of muscle fibrosis.
The Specific Aims are: to identify the direct cellular targets for signaling by MSTN and related proteins in skeletal muscle responsible for mediating effects on fibrosis, to assess the potential beneficial effects of targeting BMP-1/tolloid metalloproteases for modulating the fibrotic response in muscle, and to test biologies targeting MSTN and other TGFB family members for their ability to prevent or reverse fibrosis in mouse models of muscular dystrophy. Taken together, these studies should provide fundamental insights into the cellular and molecular mechanisms underlying the beneficial effect of MSTN loss on the pathogenesis of fibrosis and provide valuable information for translating these findings into the development of a therapeutic to combat muscle fibrosis in patients with muscle degenerative diseases.

Public Health Relevance

Fibrosis has long been recognized as a major exacerbating factor in the pathogenesis of muscle degenerative diseases. The regulatory mechanisms underlying the development of fibrosis in muscle are poorly understood, and few therapeutic strategies have been developed for combating muscle fibrosis. Here, we will investigate the potential beneficial effects of targeting myostatin and related pathways to prevent or reverse fibrosis in muscular dystrophy.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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University of Chicago
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