Abstract
Centronuclear myopathies (CNM) are congenital disorders associated with muscle weakness and abnormally located nuclei in skeletal muscle. An autosomal dominant form of CNM results from mutations in the gene encoding dynamin 2 (DNM2), and loss-of-function mutations in the gene encoding myotubularin (MTM1) result in X-linked CNM (XLCNM, also called myotubular myopathy), which promotes severe neonatal hypotonia and early death. Currently, no effective treatments exist for XLCNM. Here, we found increased DNM2 levels in XLCNM patients and a mouse model of XLCNM (Mtm1(-/y)). Generation of Mtm1(-/y) mice that were heterozygous for Dnm2 revealed that reduction of DNM2 in XLCNM mice restored life span, whole-body strength, and diaphragm function and increased muscle strength. Additionally, classic CNM-associated histological features, including fiber atrophy and nuclei mispositioning, were absent or reduced. Ultrastructural analysis revealed improvement of sarcomere organization and triad structures. Skeletal muscle-specific decrease of Dnm2 during embryogenesis or in young mice after disease onset revealed that the rescue associated with downregulation of Dnm2 is cell autonomous and is able to stop and potentially revert XLCNM progression. These data indicate that MTM1 and DNM2 regulate muscle organization and force through a common pathway. Furthermore, despite DNM2 being a key mechanoenzyme, its reduction is beneficial for XLCNM and represents a potential therapeutic approach for patients.
Highlights
Centronuclear myopathies (CNM) are a group of congenital myopathies characterized by muscle weakness, fiber atrophy, predominance of type I fibers, and increased centralization of nuclei not secondary to muscle regeneration [1, 2]
Tibialis anterior (TA) muscle mass was similar between WT and Dnm2+/– mice (Supplemental Figure 2F), and no difference in absolute or specific maximal force or fatigability of the TA was detected (Supplemental Figure 2, G–I), indicating overall that Dnm2+/– mice are clinically and physiologically similar to WT mice, with no detectable difference in muscle function
As the diaphragm is a vital muscle required for breathing, we propose that reduced dynamin 2 (DNM2) expression in the diaphragm muscle is critical for increased survival of Mtm1–/yDnm2skm+/– mice and to rescue X-linked CNM (XLCNM)
Summary
Centronuclear myopathies (CNM) are a group of congenital myopathies characterized by muscle weakness, fiber atrophy, predominance of type I fibers, and increased centralization of nuclei not secondary to muscle regeneration [1, 2]. More than 200 different mutations in MTM1 have been reported in about 450 families, most of which lead to a strong reduction of MTM1 protein [6,7,8,9]. Mtm1-knockout mice or mice with knockin of a patient mutation both recapitulate the CNM phenotype with classical histological features including abnormal organelle positioning, mislocalization of nuclei, and muscle atrophy, associated with a corresponding reduction in muscle strength [10,11,12]. A defect in triad structures associated with abnormal excitation-contraction coupling has been reported in several animal
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