Department of Molecular Biology and 2Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75930-9148, USA.
J Clin Invest. 2011 Aug;121(8):3258-68. doi: 10.1172/JCI46267.
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.
微小 RNA 通过抑制 mRNA 靶标表达来调节细胞表型。在这项研究中，我们表明肌肉特异性微小 RNA miR-133a-1 和 miR-133a-2 对于小鼠骨骼肌功能和体内平衡的多个方面都是必不可少的。miR-133a-1 和 miR-133a-2 基因缺失的小鼠在 II 型（快肌纤维）肌纤维中发生成年发病的中心核肌病，伴随着线粒体功能受损、快肌纤维向慢肌纤维转化以及肌三联体（兴奋-收缩耦联部位）排列紊乱。这些异常类似于人类中心核肌病，可以归因于 miR-133a 靶 mRNA 的失调，该 mRNA 编码的肌球蛋白 2 是一种 GTP 酶，与人类中心核肌病有关。我们的研究结果揭示了 miR-133a 在维持成人骨骼肌结构、功能、生物能量学和肌纤维特性中的重要作用；它们还确定了中心核肌病的一个潜在调节剂。
