Ramatercept

Aim: We sought to determine the sensitivity of electrical impedance myography (EIM) to myofiber hypertrophy induced by treatment with various doses of ActRIIB-mFc, an inhibitor of myostatin signaling. Methods: Wild-type C57BL/6 J mice (n = 40, male) were treated with three different doses of ActRIIB-mFc (i.e., RAP-031) or vehicle twice weekly for 5 weeks. End point assessments included gastrocnemius EIM, force measurements, muscle mass and myofiber size quantification. Results: ActRIIB-mFc increased body mass, muscle mass and myofiber size across all doses. Alterations in EIM 50 kHz phase and center frequency (fc) were also present, with trends in a dose-dependent fashion. Significant correlations between EIM parameters and myofiber/functional data were identified. Conclusion: EIM outcomes can serve as effective biomarkers of myostatin signaling inhibition, demonstrating a dose sensitivity and correlation to standard assessments.

Myostatin (MST) is a potent regulator of muscle growth and size. Spinal cord injury (SCI) results in marked atrophy of muscle below the level of injury. Currently, there is no effective pharmaceutical treatment available to prevent sublesional muscle atrophy post-SCI. To determine whether inhibition of MST with a soluble activin IIB receptor (RAP-031) prevents sublesional SCI-induced muscle atrophy, mice were randomly assigned to the following groups: Sham-SCI; SCI+Vehicle group (SCI-VEH); and SCI+RAP-031 (SCI-RAP-031). SCI was induced by complete transection at thoracic level 10. Animals were euthanized at 56 days post-surgery. RAP-031 reduced, but did not prevent, body weight loss post-SCI. RAP-031 increased total lean tissue mass compared to SCI-VEH (14.8%). RAP-031 increased forelimb muscle mass post-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 SCI-VEH groups. In the gastrocnemius, messenger RNA (mRNA) expression was elevated for interleukin (IL)-6 (8-fold), IL-1β (3-fold), and tumor necrosis factor alpha (8-fold) in the SCI-VEH, compared to the Sham group. Muscle RING finger protein 1 mRNA was 2-fold greater in the RAP-031 group, compared to Sham-SCI. RAP-031 did not influence cytokine expression. Bone mineral density of the distal femur and proximal tibia were decreased post-SCI (-26% and -28%, respectively) and were not altered by RAP-031. In conclusion, MST inhibition increased supralesional muscle mass, but did not prevent sublesional muscle or bone loss, or the inflammation in paralyzed muscle.