microRNA-133a as an indicator of disease progression and treatment response in X-linked myotubular myopathy.

X-linked myotubular myopathy (XLMTM) is a rare pediatric neuromuscular disease caused by loss-of-function variants in myotubularin (MTM1). With novel therapies entering clinical trials, the discovery of robust biomarkers that reflect disease severity and therapeutic efficacy is critically required. Using high-throughput and directed approaches, we identified a decrease in miR-133a expression as a marker of XLMTM disease in skeletal muscle and plasma of a mouse model of XLMTM (Mtm1 KO). miR-133a is a muscle-enriched non-coding RNA (myomiR) involved in muscle development and function and is implicated in the regulation of the XLMTM modifier gene DNM2. miR-133a has emerged as both a treatment-effect biomarker and therapeutic candidate in other neuromuscular diseases. We demonstrate that miR-133a expression negatively correlates with disease severity in Mtm1 KO mice and is upregulated in response to treatments that improve DNM2 expression and/or significantly rescue XLMTM. Moreover, we show that miR-133a expression in treated Mtm1 KO mice positively correlates with treatment response and was shown to have high discrimination accuracy for XLMTM by linear discriminant analysis (79%-90%) and receiver operating characteristic curve analysis (AUC >0.80). These results support miR-133a as a robust, circulating biomarker that reflects disease severity and treatment response in XLMTM.