mTOR inhibition and BMP signaling act synergistically to reduce muscle fibrosis and improve myofiber regeneration

Muscle trauma is highly morbid due to intramuscular scarring, or fibrosis, and muscle atrophy. Studies have shown that bone morphogenetic proteins (BMPs) reduce muscle atrophy. However, increased BMP signaling at muscle injury sites causes heterotopic ossification, as seen in patients with fibrodysp...

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Published inJCI insight Vol. 1; no. 20; p. e89805
Main Authors Agarwal, Shailesh, Cholok, David, Loder, Shawn, Li, John, Breuler, Christopher, Chung, Michael T, Sung, Hsiao Hsin, Ranganathan, Kavitha, Habbouche, Joe, Drake, James, Peterson, Joshua, Priest, Caitlin, Li, Shuli, Mishina, Yuji, Levi, Benjamin
Format Journal Article
LanguageEnglish
Published United States American Society for Clinical Investigation 08.12.2016
Subjects
Animals
Bone Morphogenetic Proteins - metabolism
Cell Differentiation
Cells, Cultured
Fibroblasts - cytology
Fibrosis
Humans
Mice
Mice, Transgenic
Muscle, Skeletal - physiopathology
Myositis Ossificans - metabolism
Myositis Ossificans - pathology
Ossification, Heterotopic - metabolism
Ossification, Heterotopic - pathology
Osteogenesis
Regeneration
Signal Transduction
Sirolimus - pharmacology
TOR Serine-Threonine Kinases - antagonists & inhibitors
TOR Serine-Threonine Kinases - metabolism
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Summary:Muscle trauma is highly morbid due to intramuscular scarring, or fibrosis, and muscle atrophy. Studies have shown that bone morphogenetic proteins (BMPs) reduce muscle atrophy. However, increased BMP signaling at muscle injury sites causes heterotopic ossification, as seen in patients with fibrodysplasia ossificans progressiva (FOP), or patients with surgically placed BMP implants for bone healing. We use a genetic mouse model of hyperactive BMP signaling to show the development of intramuscular fibrosis surrounding areas of ectopic bone following muscle injury. Rapamycin, which we have previously shown to eliminate ectopic ossification in this model, also eliminates fibrosis without reducing osteogenic differentiation, suggesting clinical value for patients with FOP and with BMP implants. Finally, we use reporter mice to show that BMP signaling is positively associated with myofiber cross-sectional area. These findings underscore an approach in which 2 therapeutics (rapamycin and BMP ligand) can offset each other, leading to an improved outcome.
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Authorship note: S. Agarwal and D. Cholok contributed equally to this work.
ISSN:2379-3708
2379-3708
DOI:10.1172/jci.insight.89805