Muscle Growth by Activin Type II Receptor Blocking Ameliorates Weakness in GNE Myopathy Mice

Background GNE myopathy is an autosomal recessive muscle disease clinically characterized by skeletal muscle atrophy and weakness. We have established that a key factor in the mechanism of disease is sialic acid deficiency, a target for recent and ongoing clinical trials. In GNE myopathy patients with existing severe muscle atrophy and degeneration, however, exploring additional therapeutic options may prove beneficial. Objective In this study, we demonstrate the efficacy of myostatin pathway blockade, which promotes muscle growth, on GNE myopathy model mice. Methods CDD866, a murinized anti‐activin type II receptor antibody, were administered to GNE myopathy model mice once weekly with subcutaneous injections for 8 weeks. Physiological examination and pathological observation on the skeletal muscles of treated mice were performed. Results CDD866, not only promoted body weight gain and increase in muscle size, but also led to the recovery of specific tetanic force, which is a functional indicator of muscle contractile devices. In addition, we demonstrate that increased S ‐nitrosylation of contractile and metabolic proteins leads to muscle weakness in GNE myopathy mice. More importantly, CDD866 treatment in mice reversed S ‐nitrosylation of the muscle proteins along with the recovery of muscle function. Discussion This results suggest that protein synthesis via myostatin pathway blockade has a beneficial effect by providing newly‐synthesized fresh muscle proteins to chronic myopathic muscles in addition to muscle size increment. Our results also suggest that the myostatin pathway blockade may be a promising therapy on GNE myopathy in addition to sialic acid supplementation. Support or Funding Information Intramural Research Grant (28‐6) for Neurological and Psychiatric Disorders of NCNP