Mice Lacking microRNA 133a Develop Dynamin 2–dependent Centronuclear Myopathy

J Clin Invest. 2011 Aug;121(8):3258-68. doi: 10.1172/JCI46267.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Dynamin II / metabolism*
  • Fatty Acids / metabolism
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • MicroRNAs / physiology
  • Mitochondria / metabolism
  • Muscle, Skeletal / metabolism
  • Myopathies, Structural, Congenital
  • Phenotype
  • Protein Isoforms
  • Rats

Substances

  • Fatty Acids
  • MicroRNAs
  • Mirn133 microRNA, mouse
  • Protein Isoforms
  • Dynamin II