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 2

Centronuclear myofibers in dKO skeletal muscle.

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Centronuclear myofibers in dKO skeletal muscle. (A) H&E staining of ...
(A) H&E staining of soleus, EDL, G/P, and TA muscles of WT and dKO mice at 12 weeks of age. Scale bars: 40 μm. (B) Immunostaining of TA muscle against laminin. Nuclei are stained with DAPI. dKO TA muscle showed central nuclei. Scale bars: 40 μm. (C) Percentage of centronuclear myofibers in 4 WT mice and 10 dKO mice at 12 weeks of age. For each mouse, more than 500 myofibers were counted for TA and G/P muscles and more than 300 myofibers were counted for soleus and EDL muscles. (D) NADH-TR staining of dKO TA muscle revealed abnormal distribution, radiating intermyofibrillary network (arrows), and ring-like fibers (asterisks). Scale bars: 20 μm. (E) EBD uptake of TA muscles of WT, dKO, and mdx mice. Immunostaining with laminin (green) is shown; EBD is detected as a red signal under fluorescence microscopy. Scale bars: 100 μm. (F) Expression of myogenic genes and of embryonic MHC (Myh3) and perinatal MHC (Myh8) in WT and dKO TA muscle, determined by real-time RT-PCR. n = 3 (WT and dKO).