Myostatin: a Circulating Biomarker Correlating with Disease in Myotubular Myopathy Mice and Patients

Abstract

Myotubular myopathy, also called X-linked centronuclear myopathy (XL-CNM), is a severe congenital disease targeted for therapeutic trials. To date, biomarkers to monitor disease progression and therapy efficacy are lacking. The Mtm1 À/y mouse is a faithful model for XL-CNM, due to myotubularin 1 (MTM1) loss-of-function mutations. Using both an unbiased approach (RNA sequencing [RNA-seq]) and a directed approach (qRT-PCR and protein level), we identified decreased Mstn levels in Mtm1 À/y muscle, leading to low levels of myostatin in muscle and plasma. Myostatin (Mstn or growth differentiation factor 8 [Gdf8]) is a protein released by myocytes and inhibiting muscle growth and differentiation. Decreasing Dnm2 by genetic cross with Dnm2 +/À mice or by antisense oligonucleotides blocked or postponed disease progression and resulted in an increase in circulating myostatin. In addition, plasma myostatin levels inversely correlated with disease severity and with Dnm2 mRNA levels in muscles. Altered Mstn levels were associated with a generalized disruption of the myostatin pathway. Importantly, in two different forms of CNMs we identified reduced circulating myostatin levels in plasma from patients. This provides evidence of a blood-based biomarker that may be used to monitor disease state in XL-CNM mice and patients and supports monitoring circulating myostatin during clinical trials for myotubular myopathy.

Myostatin as a Biomarker of Muscle Wasting and other Pathologies-State of the Art and Knowledge Gaps

“…A study by Burch et al, indicates that decreased serum myostatin levels in muscle pathologies are associated with disease progression [ 100 ], which can be explained by the down-regulation of myostatin pathway in order to compensate for muscle wasting or atrophy [ 101 ]. Further research present myostatin as a feasible biomarker for disease progression, severity and treatment efficacy in mice and patients with myotubular myopathy [ 102 ], as well as for estimating a therapeutic response to pharmaco-gene therapy in Duchenne muscular dystrophy [ 103 ]. A similar mechanism emerges in idiopathic inflammatory myopathies.…”

Common Pathogenic Mechanisms in Centronuclear and Myotubular Myopathies and Latest Treatment Advances

“…Myostatin inhibitors were also shown to be beneficial in DMD mouse models, but this positive impact has not been later translated in clinical studies [ 258 ]. Potentially, this low benefit in XLMTM could be due to the low myostatin plasma levels found in sick Mtm1 −/y mice and observed in XLMTM and ADCNM patients [ 259 , 260 ].…”

Multi-omics comparisons of different forms of centronuclear myopathies and the effects of several therapeutic strategies

“…46 In agreement, MSTN was recently found decreased in plasma from MTM1-and DNM2-CNM patients and responded to ASO Dnm2 treatment in Mtm1 À/y mice. 69 In addition, MSTN plasma level was also normalized upon BIN1 overexpression (Figure 7C). ANXA2 is a calcium-dependent phospholipid-binding protein that has a role in muscle repair, 70 and it was validated here as a muscle biomarker for all of the CNM forms that we have tested.…”