Mice lacking microRNA 133a develop dynamin 2–dependent centronuclear myopathy
Ning Liu, … , Rhonda Bassel-Duby, Eric N. Olson
Ning Liu, … , Rhonda Bassel-Duby, Eric N. Olson
Published July 1, 2011
Citation Information: J Clin Invest. 2011;121(8):3258-3268. https://doi.org/10.1172/JCI46267.
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Research Article Muscle biology

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.

Authors

Ning Liu, Svetlana Bezprozvannaya, John M. Shelton, Madlyn I. Frisard, Matthew W. Hulver, Ryan P. McMillan, Yaru Wu, Kevin A. Voelker, Robert W. Grange, James A. Richardson, Rhonda Bassel-Duby, Eric N. Olson

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Figure 3

Disorganization of triads in TA muscle fibers in dKO mice.

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Disorganization of triads in TA muscle fibers in dKO mice. (A) Expressio...
(A) Expression of mRNA transcripts encoding components of T-tubules and SR was determined by real-time RT-PCR in TA muscles of 12-week-old mice. n = 3 (WT and dKO). (B) Immunostaining of T-tubules and SR in transverse sections of TA muscle from WT and dKO mice at 12 weeks of age. T-tubules were detected by anti-DHPRα, and terminal cisternae of the SR were detected by anti-RyR1. Nuclei were detected by DAPI, and the myofiber perimeter was stained by anti-laminin. Images of multiple levels of the sections were taken and reconstructed to create the 3D effect. Scale bars: 30 μm. (C–J) Electron micrographs of WT and dKO muscle. dKO TA muscle showed accumulation of electron-dense structures (D–F) that were absent in WT TA muscle (C). dKO muscle (H and J) displayed T-tubules (arrows) in abnormal orientations compared with WT muscle (G and I). Scale bars: 2 μm (C and D); 0.5 μm (E–H); 0.2 μm (I and J).