Recombinant Myostatin (GDF-8) Propeptide Enhances the Repair and Regeneration of Both Muscle and Bone in a Model of Deep Penetrant Musculoskeletal Injury
- 1 September 2010
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in The Journal of Trauma and Acute Care Surgery
- Vol. 69 (3), 579-583
- https://doi.org/10.1097/ta.0b013e3181c451f4
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.This publication has 41 references indexed in Scilit:
- Myostatin (GDF-8) deficiency increases fracture callus size, Sox-5 expression, and callus bone volumeBone, 2009
- Relationships between Transforming Growth Factor-β1, Myostatin, and DecorinOnline Journal of Public Health Informatics, 2007
- Loss of myostatin (GDF8) function increases osteogenic differentiation of bone marrow-derived mesenchymal stem cells but the osteogenic effect is ablated with unloadingBone, 2007
- A Mutation in the Myostatin Gene Increases Muscle Mass and Enhances Racing Performance in Heterozygote DogsPLoS Genetics, 2007
- Application of Histomorphometric Methods to the Study of Bone RepairJournal of Bone and Mineral Research, 2005
- Myostatin Mutation Associated with Gross Muscle Hypertrophy in a ChildThe New England Journal of Medicine, 2004
- Increased bone mineral density in the femora of GDF8 knockout miceThe Anatomical Record Part A: Discoveries in Molecular, Cellular, and Evolutionary Biology, 2003
- Poor muscle coverage delays fracture healing in ratsActa Orthopaedica, 2002
- Immunohistochemical detection of activin A, follistatin, and activin receptors during fracture healing in the ratJournal of Orthopaedic Research, 1998
- Regulation of skeletal muscle mass in mice by a new TGF-p superfamily memberNature, 1997