Abstract
Mutations in the myotubularin 1 (MTM1) gene can cause the fatal disease X-linked centronuclear myopathy (XLCNM), but the underlying mechanism is incompletely understood. In this report, using an Mtm1 -/y disease model, we found that expression of the intragenic microRNA miR-199a-1 is up-regulated along with that of its host gene, dynamin 2 (Dnm2), in XLCNM skeletal muscle. To assess the role of miR-199a-1 in XLCNM, we crossed miR-199a-1 -/- with Mtm1 -/y mice and found that the resultant miR-199a-1-Mtm1 double-knockout mice display markers of improved health, as evidenced by lifespans prolonged by 30% and improved muscle strength and histology. Mechanistic analyses showed that miR-199a-1 directly targets nonmuscle myosin IIA (NM IIA) expression and, hence, inhibits muscle postnatal development as well as muscle maturation. Further analysis revealed that increased expression and phosphorylation of signal transducer and activator of transcription 3 (STAT3) up-regulates Dnm2/miR-199a-1 expression in XLCNM muscle. Our results suggest that miR-199a-1 has a critical role in XLCNM pathology and imply that this microRNA could be targeted in therapies to manage XLCNM.
Highlights
Mutations in the myotubularin 1 (MTM1) gene can cause the fatal disease X-linked centronuclear myopathy (XLCNM), but the underlying mechanism is incompletely understood
Upon transfecting HEK 293T cells with the reporters, we found that luciferase activity was significantly reduced in the signal transducer and activator of transcription 3 (Stat3)-binding site mutant groups compared with the intact group (ϳ50%; Fig. 7C)
We found that, during the pathological process, the dynamin 2 (DNM2) gene, along with its intragenic miR-199a-1, was secondarily up-regulated in XLCNM muscle
Summary
In this report, using an Mtm1؊/y disease model, we found that expression of the intragenic microRNA miR-199a-1 is up-regulated along with that of its host gene, dynamin 2 (Dnm2), in XLCNM skeletal muscle. Centronuclear myopathies (CNMs) are a series of fatal muscle diseases with muscular pathology characterized by atrophic muscle fibers, disordered sarcomere organization, and a large number of centronuclear myofibers [1] Among these diseases, X-linked CNM is associated with the most severe form of myopathies, and most patients die in the first year after birth due to respiratory failure of muscle weakness [2]. CNMs are caused by mutations in several genes, including myotubularin 1 (MTM1), dynamin 2 (DNM2), bridging integrator-1 (BIN1), ryanodine receptor (RYR1), and titin (TTN). Our study revealed an important role for an intragenic microRNA in XLCNM pathological progression
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
