Duchenne muscular dystrophy (DMD) is a genetic myopathy caused by mutations that result in the loss of functional dystrophin. This destabilizes the muscle, leading to cyclic damage and impaired regeneration, eventually resulting in the buildup of intramuscular inflammation, fibrosis and fat. The progressive loss of muscle strength and chronic use of glucocorticoids result in osteopenia and high fracture risk. KER-065 is an investigational, modified ActRII-Fc ligand trap designed to inhibit activins A and B and myostatin to promote functional muscle and bone growth. RKER-065, the research form of KER-065, has increased muscle mass and functional strength in wild-type mice, in part through enhancing satellite cell self-renewal and differentiation towards myoblasts. When tested in the D2.mdx mouse model of DMD, RKER-065 monotherapy resulted in the preservation of lean muscle mass and strength, accompanied by improvements in bone structural morphology. Further analysis of the muscle revealed that RKER-065 was able to reduce the M1/M2 macrophage ratio, supportive of reduced inflammation and promotion of muscle regeneration and stability. Additionally, when combined with glucocorticoids, the standard of care in DMD, RKER-065 was able to counteract the effects of steroids ability to induce muscle and bone loss. Finally, we have observed that RKER-065 can be complementary to the phosphorodiamidate morpholino oligomers (PMO) approach to exon skipping. Indeed, D2.mdx mice that were treated with a combination of RKER-065 and PMO had improved exon skipping efficiency (determined by PCR), increased rescue of dystrophin protein and significantly improved grip strength compared to those treated with PMO alone. Taken together, these data highlight beneficial pleiotropic effects of RKER-065 on muscle and bone in D2.mdx mice, as well as synergistic results when combined with approved therapeutic approaches. These dual therapy approaches could offer a promising treatment strategy to improve outcomes in patients with DMD by targeting complementary pathways.