Mice lacking microRNA 133a develop dynamin 2–dependent centronuclear myopathy

Abstract

MicroRNAs modulate cellular phenotypes by inhibiting expression of mRNA targets. In this study, we have shown that the muscle-specific microRNAs miR-133a-1 and miR-133a-2 are essential for multiple facets of skeletal muscle function and homeostasis in mice. Mice with genetic deletions of miR-133a-1 and miR-133a-2 developed adult-onset centronuclear myopathy in type II (fast-twitch) myofibers, accompanied by impaired mitochondrial function, fast-to-slow myofiber conversion, and disarray of muscle triads (sites of excitation-contraction coupling). These abnormalities mimicked human centronuclear myopathies and could be ascribed, at least in part, to dysregulation of the miR-133a target mRNA that encodes dynamin 2, a GTPase implicated in human centronuclear myopathy. Our findings reveal an essential role for miR-133a in the maintenance of adult skeletal muscle structure, function, bioenergetics, and myofiber identity; they also identify a potential modulator of centronuclear myopathies.

Histone deacetylases 1 and 2 regulate autophagy flux and skeletal muscle homeostasis in mice

“…H&E staining, NADH staining, metachromatic ATPase staining, Evans blue dye uptake experiments, succinic dehydrogenase staining, and immunohistochemistry were performed as previously described (50)(51)(52)(53). More information is provided in SI Methods.…”

“…Western blot analyses were performed on TA muscles as previously described (52). More information is provided in SI Methods.…”

Roles of the canonical myomiRs miR-1, -133 and -206 in cell development and disease

“…In vivo, the deletion of both miR-133a1/2 genes causes lethal cardiac (ventricularseptal) abnormalities in about half of the mouse embryos or neonates, while mice deficient in only one of either miR133a1 or 133a2 have phenotypically normal hearts [14] . Skeletal muscles are normal in both double and single mutant miR133a mice (dead and surviving), implying that miR133b can replace the absent miR133a species in skeletal muscle and continue the regulation of normal development.…”

“…Skeletal muscles are normal in both double and single mutant miR133a mice (dead and surviving), implying that miR133b can replace the absent miR133a species in skeletal muscle and continue the regulation of normal development. In double mutant mice lacking all miR133a, smooth muscle gene expression was activated 2-4 × and cardiomyocytes (but not cardio-fibroblasts) proliferated 2.5 × faster than normal, accompanied by increased expression of miR133a targets, including PTBP2, CDC42, cell cycle control factors and cyclins D1, D2 and B1 [14] . Recently, both adult and neona tal human foreskin fibroblasts were found capable of being reprogrammed towards cardiac muscle by exogenous expression of only several factors, myocardin, HAND2, Tbox5, GATA4, and miR1, miR 133a and miR499 [15] .…”

A non-conserved miRNA regulates lysosomal function and impacts on a human lysosomal storage disorder

“…These singlestranded RNAs are post-transcriptional gene regulators, which have received much attention due to their critical regulatory impact on biological functions related to development, proliferation, stress signalling and metabolism 15,16 . Although many miRNAs have modest effects on gene expression, several studies have elucidated major regulatory functions for miRNAs, including the miR-17-92/miR-106b-25 clusters in embryonic development 17 and miR-133 in cardiac and skeletal muscle development 18,19 . Not surprisingly, miRNAs have been causally linked to diseases ranging from neurological disorders and infectious diseases to metabolic disorders and cancers 20 .…”