title: mTOR inhibition and BMP signaling act synergistically to reduce muscle fibrosis and improve myofiber regeneration.
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.affiliation: Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan, USA.
authors.forename: Shailesh
authors.initials: S
authors.lastname: Agarwal
authors.affiliation: Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan, USA.
authors.forename: David
authors.initials: D
authors.lastname: Cholok
authors.affiliation: Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan, USA.
authors.forename: Shawn
authors.initials: S
authors.lastname: Loder
authors.affiliation: Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan, USA.
authors.forename: John
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Breuler
authors.affiliation: Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Chung
authors.affiliation: Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan, USA.
authors.forename: Hsiao Hsin
authors.initials: HH
authors.lastname: Sung
authors.affiliation: Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan, USA.
authors.forename: Kavitha
authors.initials: K
authors.lastname: Ranganathan
authors.affiliation: Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan, USA.
authors.forename: Joe
authors.initials: J
authors.lastname: Habbouche
authors.affiliation: Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan, USA.
authors.forename: James
authors.initials: J
authors.lastname: Drake
authors.affiliation: Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Peterson
authors.affiliation: Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan, USA.
authors.forename: Caitlin
authors.initials: C
authors.lastname: Priest
authors.affiliation: Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan, USA.
authors.forename: Shuli
authors.initials: S
authors.lastname: Li
authors.affiliation: School of Dentistry, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Mishina
authors.affiliation: Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Levi
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology; D005355:Fibrosis; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000503:physiopathology; D009221:Myositis Ossificans / Q000378:metabolism / Q000473:pathology*; D009999:Ossification, Heterotopic / Q000378:metabolism / Q000473:pathology*; D010012:Osteogenesis; D012038:Regeneration; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D019485:Bone Morphogenetic Proteins; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus