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. 2010 Sep;69(3):579-83.
doi: 10.1097/TA.0b013e3181c451f4.

Recombinant myostatin (GDF-8) propeptide enhances the repair and regeneration of both muscle and bone in a model of deep penetrant musculoskeletal injury

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Recombinant myostatin (GDF-8) propeptide enhances the repair and regeneration of both muscle and bone in a model of deep penetrant musculoskeletal injury

Mark W Hamrick et al. J Trauma. 2010 Sep.

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.

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Figures

Fig. 1
Fig. 1
(a) Mice received treatments on the day of surgery, 5 days post-op, 10 days post-op, and were euthanized 15 days following the initial treatment. (b) A fibula osteotomy procedure was used (arrow) and the lateral compartment muscles were cut. Fib-fibula, Tib-tibia, TA-tibialis anterior. (c) Histological sections at the osteotomy site were stained using Masson trichrome and 0.80 mm2 region of interest lateral to the fracture callus examined for fraction of fibrotic tissue (blue). (d) Body weight and (e) muscle mass (b; triceps brachii + quadriceps femoris) in saline (VEH) and propeptide (PROP; 20 mg/kg) treated mice. Error bars represent S.D.
Fig. 2
Fig. 2
(a) MicroCT images of the fibula osteotomy site in saline (VEH) and propeptide (PROP; 20 mg/kg) treated mice. Note extensive bridging across the osteotomy gap in the propeptide-treated animals. (b) Bony bridging across the osteotomy gap is increased significantly in the propeptide (PROP) treated mice, and (c) bone volume of the fracture callus is increased significantly in the propeptide (PROP) treated mice.
Fig. 3
Fig. 3
(a) Cartilage area, as indicated by safranin-O staining, is increased in fracture callus of propeptide (PROP)-treated mice (b).
Fig. 4
Fig. 4
(a) Masson trichrome staining of the soft-tissue injury site lateral to the fracture callus showing greater fibrotic tissue staining (blue, left panel) in the vehicle (VEH) treated animal compared to greater muscle staining (red, right panel) in the propeptide (PROP) treated animal. (b) Quantification of red and blue pixel fractions, where a value of 250 is either pure red or pure blue), indicates a significant increase in the fraction of red (muscle) pixels and decrease in blue (fibrous tissue) pixels with propeptide (PROP) treatment.

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