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mTOR inhibition and BMP signaling act synergistically to reduce muscle fibrosis and improve myofiber regeneration
Shailesh Agarwal, … , Yuji Mishina, Benjamin Levi
Shailesh Agarwal, … , Yuji Mishina, Benjamin Levi
Published December 8, 2016
Citation Information: JCI Insight. 2016;1(20):e89805. https://doi.org/10.1172/jci.insight.89805.
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Research Article Inflammation Therapeutics

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

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Abstract

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.

Authors

Shailesh Agarwal, David Cholok, Shawn Loder, John Li, Christopher Breuler, Michael T. Chung, Hsiao Hsin Sung, Kavitha Ranganathan, Joe Habbouche, James Drake, Joshua Peterson, Caitlin Priest, Shuli Li, Yuji Mishina, Benjamin Levi

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Figure 1

Myofiber injury and fibrosis surround the ectopic osseous lesion in a mouse model of hyperactive BMP signaling and local muscle injury.

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Myofiber injury and fibrosis surround the ectopic osseous lesion in a mo...
(A) Transgenic mouse model (caAcvr1fl/fl) with activation of hyperactive BMP signaling after local adenoviral Cre (Ad.cre) injection. (B) Area of myofiber injury with centralized nuclei in wild-type mice 20 days after Ad.cre and cardiotoxin (CTX) injury (black arrowheads indicate myofibers with centralized nuclei). (C) Fibrosis corresponding with regions of myofiber injury in wild-type mice 20 days after Ad.cre/CTX injury (green arrowheads indicate fascial plane, blue arrowheads indicate fibrosis). (D) Increased fibrosis staining based on picrosirius red staining in caAcvr1fl/fl mice when compared with wild-type mice 20 days after Ad.cre/CTX injury (normalized ratio: 5.14 vs. 1.0, P < 0.05, Student’s 2-tailed t test, n = 3). (E) Increased ratio of collagen 1 (Col1a1) mRNA expression in injured muscle harvested from untreated caAcvr1fl/fl mice when compared with wild-type mice (2.73 vs. 1.32, Student’s 2-tailed t test, n = 6). (F) Representative immunostaining for platelet-derived growth factor receptor α (PDGFRA) in wild-type and caAcvr1fl/fl mice 20 days after Ad.cre/CTX injury (white arrowheads indicate PDGFRA+ cells). (G) Gating strategy for FACS analysis to quantify PDGFRA+CD45+ (hematopoietic origin) and PDGFRA+CD45– (nonhematopoietic) mesenchymal cells in Ad.cre/CTX-injected wild-type and caAcvr1fl/fl mice. (H) Increased PDGFRA+CD45+ (normalized ratio: 3.7 vs. 1.0, P < 0.05, Student’s 2-tailed t test, n = 4) and PDGFRA+CD45– (normalized ratio: 8.2 vs. 1.0, P < 0.05) mesenchymal cells in hindlimbs of caAcvr1fl/fl mice relative to wild-type mice 20 days after Ad.cre/CTX injury. SSC, side scatter. All scale bars: 200 μm. *P < 0.05.

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