EC.O.4 - Reversible endogenous downregulation of myostatin pathway in wasting neuromuscular diseases explains challenges of anti-myostatin therapeutic approaches

Abstract

Muscular dystrophies are characterized by weakness and wasting of skeletal muscle tissues and treating wasting muscle is one of the biggest issues in the neuromuscular field. Several drugs targeting the myostatin pathway have been used in clinical trials to increase muscle mass and function but so far, most drugs had no or limited effects in improving function in neuromuscular patients. In our study, the expression levels of different actors of the myostatin network were analysed at mRNA and protein levels in neuromuscular patients' sera and skeletal muscle specimens. In muscle wasting or atrophying diseases, a strong down-regulation of the whole myostatin pathway was observed with a decrease of myostatin and activin receptor, and an increase of the myostatin antagonist, follistatin. We also provide in vivo evidence in the congenital myopathy mtm1 mouse model that a down-regulated myostatin pathway can be reactivated by correcting the underlying gene defect using AAV-mediated gene therapy. Importantly, we show that the MTM1 restoration effect on muscle mass can be further enhanced by anti-myostatin therapy. Our data may explain the poor clinical efficacy of anti-myostatin approaches in clinical studies and the apparent contradictory results in mice regarding the efficacy of anti-myostatin approaches and may profoundly affect patient selection and stratification for future trials.