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

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 mouse is a faithful model for XL-CNM, due to myotubularin 1 () 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 levels in muscle, leading to low levels of myostatin in muscle and plasma. Myostatin ( or growth differentiation factor 8 []) is a protein released by myocytes and inhibiting muscle growth and differentiation. Decreasing by genetic cross with 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 mRNA levels in muscles. Altered 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.