Graduate School of Comprehensive Human Science, University of Tsukuba , Tsukuba , Japan.
Division of Regenerative Medical Engineering, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo , Tokyo , Japan.
Am J Physiol Cell Physiol. 2019 Feb 1;316(2):C285-C292. doi: 10.1152/ajpcell.00278.2018. Epub 2018 Dec 12.
The contractile and metabolic properties of adult skeletal muscle change in response to endurance exercise. The mechanisms of transcriptional regulation in exercise-induced skeletal muscle adaptation, including fiber-type switching and mitochondrial biogenesis, have been investigated intensively, whereas the role of microRNA (miRNA)-mediated posttranscriptional gene regulation is less well understood. We used tamoxifen-inducible Dicer1 knockout (iDicer KO) mice to reduce the global expression of miRNAs in adult skeletal muscle and subjected these mice to 2 wk of voluntary wheel running. Dicer mRNA expression was completely depleted in fast-twitch plantaris muscle after tamoxifen injection. However, several muscle-enriched miRNAs, including miR-1 and miR-133a, were reduced by only 30-50% in both the slow and fast muscles. The endurance exercise-induced changes that occurred for many parameters (i.e., fast-to-slow fiber-type switch and increases in succinate dehydrogenase, respiratory chain complex II, and citrate synthase activity) in wild type (WT) also occurred in the iDicer KO mice. Protein expression of myosin heavy chain IIa, peroxisome proliferator-activated receptor-γ coactivator-1α, and cytochrome c complex IV was also increased in the iDicer KO mice by the voluntary running. Furthermore, there was no significant difference in oxygen consumption rate in the isolated mitochondria between the WT and iDicer KO mice. These data indicate that muscle-enriched miRNAs were detectable even after 4 wk of tamoxifen treatment and there was no apparent specific endurance-exercise-induced muscle phenotype in the iDicer KO mice.
成年骨骼肌的收缩和代谢特性会对耐力运动做出响应而发生改变。人们已经深入研究了转录调控在运动诱导的骨骼肌适应中的机制，包括纤维类型转换和线粒体生物发生，而 miRNA（microRNA）介导的转录后基因调控的作用则了解较少。我们使用他莫昔芬诱导的 Dicer1 敲除（iDicer KO）小鼠来降低成年骨骼肌中 miRNAs 的总体表达，并让这些小鼠进行 2 周的自愿轮跑。在他莫昔芬注射后，快速抽搐的比目鱼肌中的 Dicer mRNA 表达完全耗尽。然而，几种肌肉特异性 miRNA，包括 miR-1 和 miR-133a，在慢肌和快肌中的表达仅减少了 30-50%。许多参数（即快速到慢速纤维类型转换以及琥珀酸脱氢酶、呼吸链复合物 II 和柠檬酸合酶活性的增加）在野生型（WT）中的耐力运动诱导变化也发生在 iDicer KO 小鼠中。在 iDicer KO 小鼠中，肌球蛋白重链 IIa、过氧化物酶体增殖物激活受体-γ 共激活因子-1α 和细胞色素 c 复合物 IV 的蛋白表达也因自愿跑步而增加。此外，WT 和 iDicer KO 小鼠之间的分离线粒体的耗氧率没有明显差异。这些数据表明，即使经过 4 周的他莫昔芬处理，肌肉特异性 miRNAs 仍然可以检测到，并且在 iDicer KO 小鼠中没有明显的特定的耐力运动诱导的肌肉表型。
