TY - JOUR
T1 - mTOR inhibition and BMP signaling act synergistically to reduce muscle fibrosis and improve myofiber regeneration
AU - Agarwal, Shailesh
AU - Cholok, David
AU - Loder, Shawn
AU - Li, John
AU - Breuler, Christopher
AU - Chung, Michael T.
AU - Sung, Hsiao Hsin
AU - Ranganathan, Kavitha
AU - Habbouche, Joe
AU - Drake, James
AU - Peterson, Joshua
AU - Priest, Caitlin
AU - Li, Shuli
AU - Mishina, Yuji
AU - Levi, Benjamin
N1 - Funding Information:
The authors would like to thank the staff at the University of Michigan Microscopy and Imaging Laboratory (MIL), and Center for Molecular Imaging (CMI) cores, particularly Amanda Fair. SA was supported by a Coller Surgical Society Research Fellowship, the NIH Loan Repayment Program, NIH grant F32AR06649901A1, and the Plastic Surgery Foundation. SL was supported by the Howard Hughes Medical Institute (HHMI) Medical Fellows Program. KR was supported by NIH grant F32 AR068902. BL was supported by funding from the NIH/National Institute of General Medical Sciences grant K08GM109105-0, an American Association of Plastic Surgery Academic Scholarship and joint PSF Pilot Award, an Association for Academic Surgery Roslyn Award, an American Association for the Surgery of Trauma Research & Education Foundation Scholarship, and the International FOP Association.
Publisher Copyright:
© 2016 American Society for Clinical Investigation. All rights reserved.
PY - 2016/12/8
Y1 - 2016/12/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85055603170&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85055603170&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.89805
DO - 10.1172/jci.insight.89805
M3 - Article
C2 - 27942591
AN - SCOPUS:85055603170
SN - 2379-3708
VL - 20
JO - JCI insight
JF - JCI insight
IS - 1
M1 - e89805
ER -