Downregulation of myostatin pathway in neuromuscular diseases may explain challenges of anti-myostatin therapeutic approaches

Abstract

Muscular dystrophies are characterized by weakness and wasting of skeletal muscle tissues. Several drugs targeting the myostatin pathway have been used in clinical trials to increase muscle mass and function but most showed limited efficacy. Here we show that the expression of components of the myostatin signaling pathway is downregulated in muscle wasting or atrophying diseases, 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 myotubular myopathy mouse model (knock-out for the myotubularin coding gene Mtm1) that a down-regulated myostatin pathway can be reactivated by correcting the underlying gene defect. Our data may explain the poor clinical efficacy of anti-myostatin approaches in several of the clinical studies and the apparent contradictory results in mice regarding the efficacy of anti-myostatin approaches and may inform patient selection and stratification for future trials.

AAV-mediated gene transfer restores a normal muscle transcriptome in a canine model of X-linked myotubular myopathy

“…More recently, these mice were co-injected with a rAAV vector coding for an inhibitory myostatin propeptide in addition to rAAV-Mtm1, and this led to a further increase in muscle mass than mice treated with rAAV-Mtm1 only (Mariot et al, 2017). This demonstrates that the tools created in this study have the potential to identify relevant targets for combinatorial gene therapy applications.…”

“…In XLMTM mice, this has been correlated with deregulated PI3K/Akt/mTOR signalling and abnormal autophagy (Al-Qusairi et al, 2013, Fetalvero, Yu et al, 2013, Joubert, Vignaud et al, 2013, Lawlor, Viola et al, 2014. More recently, another study reported the downregulation of the myostatin pathway in Mtm1-KO mice, which could be a compensatory mechanism to counter muscle hypotrophy (Mariot et al, 2017). Here, the genes coding for myostatin (MSTN) and follistatin (FST) were respectively found down-and up-regulated in XLMTM dogs, confirming the involvement of this pathway downstream of myotubularin deficiency (Appendix Figure 2), and its potential as a therapeutic target.…”

“…To our knowledge, this is the first reported comprehensive transcriptome profiling from myotubularin-deficient muscles. Previously, individual genes were queried in Mtm1-deficient mice as an attempt to explain clinical observations, (Al-Qusairi, Prokic et al, 2013, Dowling, Joubert et al, 2012, Mariot, Joubert et al, 2017. In addition, muscle biopsies from 8 XLMTM patients have been analysed for the expression of 4,200 genes using microarray and pointed to the upregulation of genes coding for cytoskeletal and extracellular matrix proteins (Noguchi, Fujita et al, 2005).…”

Myostatin inhibition in combination with antisense oligonucleotide therapy improves outcomes in spinal muscular atrophy

“…Lower level of circulating myostatin was recently reported in serum from untreated SMA patients and individuals with other dystrophic conditions . This may explain for the unsatisfactory clinical efficacy of anti‐myostatin approaches in a number of clinical trials for muscular dystrophies.…”

“…However, the relevance of these findings for DMD patients has been questioned, following the failure to meet the clinical endpoint in a recent clinical trial using a myostatin‐neutralizing antibody (NCT02310763). This has been ascribed, at least partially, to lower levels of circulating myostatin in patients with DMD, and the lack of sufficient activation of this pathway to justify its further inhibition …”