A Soluble Myostatin Inhibitor Does Not Prevent Sublesional Muscle Atrophy 56 Days After Spinal Cord Injury In Mice

Myostatin (MST) is a potent regulator of muscle growth and size. Lack of a functional MST gene leads to “double muscling” while increases in MST concentrations result in muscle atrophy. Spinal cord injury (SCI) results in marked atrophy of muscle below the injury and a slow to fast fiber-type transformation. Collectively, this results in weakened muscle contractions and highly fatiguable muscle fibers. Currently, no effective pharmaceutical treatment is available to cure or prevent sublesional muscle atrophy following SCI. PURPOSE: The purpose of this study was to determine if inhibition of MST with a soluble activin IIB receptor (RAP-031) would prevent sublesional SCI-induced muscle atrophy compared to Sham or vehicle-only groups. METHODS: Mice were randomly placed in a Sham group, an SCI+Vehicle group (VEH) or SCI+RAP-031 (RAP-031; 10 mg/kg twice a week). SCI was induced by complete transection at T10. Animals were euthanized at 56 days after surgery. RESULTS: RAP-031 reduced, but did not prevent body weight loss after SCI. RAP-031 increased total lean tissue mass compared to VEH (14.8%) but did not alter fat mass (1%). RAP-031 increased forelimb muscle mass after SCI by 38% and 19% for biceps and triceps, respectively (p<0.001). There were no differences in hindlimb muscle weights between the RAP-031 and VEH groups. In the gastrocnemius, mRNA expression was elevated for IL-6 (6-fold) and IL-12β (15-fold) in both SCI groups compared to the Sham group. Additionally, in the gastrocnemius, mRNA of TNFα was elevated 5-fold in the RAP-031 group compared to the Sham group but was not altered in the VEH group; mRNA expression of IL-1β and IL-12α was not different between any of the groups. Bone mineral density (BMD) of the metaphyses of the distal femur and proximal tibia was decreased following SCI (-26%, -28%, respectively) and was not altered by RAP-031. CONCLUSION: MST inhibition increased supralesional muscle mass but did not prevent sublesional muscle mass or bone loss, or the inflammation in paralyzed muscle.