title: Recombinant myostatin (GDF-8) propeptide enhances the repair and regeneration of both muscle and bone in a model of deep penetrant musculoskeletal injury.
abstract: BACKGROUND
  Myostatin (GDF-8) is known as a potent inhibitor of muscle growth and development, and myostatin is also expressed early in the fracture healing process. The purpose of this study was to test the hypothesis that a new myostatin inhibitor, a recombinant myostatin propeptide, can enhance the repair and regeneration of both muscle and bone in cases of deep penetrant injury.
  
  
  METHODS
  We used a fibula osteotomy model with associated damage to lateral compartment muscles (fibularis longus and brevis) in mice to test the hypothesis that blocking active myostatin with systemic injections of a recombinant myostatin propeptide would improve muscle and bone repair. Mice were assigned to two treatment groups after undergoing a fibula osteotomy: those receiving either vehicle (saline) or recombinant myostatin propeptide (20 mg/kg). Mice received one injection on the day of surgery, another injection 5 days after surgery, and a third injection 10 days after surgery. Mice were killed 15 days after the osteotomy procedure. Bone repair was assessed using microcomputed tomography (micro-CT) and histologic evaluation of the fracture callus. Muscle healing was assessed using Masson trichrome staining of the injury site, and image analysis was used to quantify the degree of fibrosis and muscle regeneration.
  
  
  RESULTS
  Three propeptide injections over a period of 15 days increased body mass by 7% and increased muscle mass by almost 20% (p < 0.001). Micro-CT analysis of the osteotomy site shows that by 15 days postosteotomy, bony callus tissue was observed bridging the osteotomy gap in 80% of the propeptide-treated mice but only 40% of the control (vehicle)-treated mice (p < 0.01). Micro-CT quantification shows that bone volume of the fracture callus was increased by ∼ 30% (p < 0.05) with propeptide treatment, and the increase in bone volume was accompanied by a significant increase in cartilage area (p = 0.01). Propeptide treatment significantly decreased the fraction of fibrous tissue in the wound site and increased the fraction of muscle relative to fibrous tissue by 20% (p < 0.01).
  
  
  CONCLUSIONS
  Blocking myostatin signaling in the injured limb improves fracture healing and enhances muscle regeneration. These data suggest that myostatin inhibitors may be effective for improving wound repair in cases of orthopaedic trauma and extremity injury.
authors.affiliation: Department of Cellular Biology and Anatomy, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, Georgia 30912, USA. mhamrick@mail.mcg.edu
authors.forename: Mark W
authors.initials: MW
authors.lastname: Hamrick
authors.forename: Phonepasong
authors.initials: P
authors.lastname: Arounleut
authors.forename: Ethan
authors.initials: E
authors.lastname: Kellum
authors.forename: Matthew
authors.initials: M
authors.lastname: Cain
authors.forename: David
authors.initials: D
authors.lastname: Immel
authors.forename: Li-Fang
authors.initials: LF
authors.lastname: Liang
mesh_terms: D000818:Animals; D001861:Bone Regeneration / Q000187:drug effects; D001842:Bone and Bones / Q000187:drug effects / Q000293:injuries*; D004195:Disease Models, Animal; D050723:Fractures, Bone / Q000188:drug therapy; D008297:Male; D051379:Mice; D009132:Muscles / Q000187:drug effects / Q000293:injuries*; D055435:Myostatin / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D010027:Osteotomy; D011994:Recombinant Proteins / Q000627:therapeutic use; D014945:Wound Healing / Q000187:drug effects*; D014950:Wounds, Penetrating / Q000188:drug therapy*; D055114:X-Ray Microtomography
chemical_list: C525912:Mstn protein, mouse; D055435:Myostatin; D011994:Recombinant Proteins