Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
Research Fellow of the Japan Society for the Promotion of Science, Tokyo, Japan.
Physiol Rep. 2021 Mar;9(5):e14789. doi: 10.14814/phy2.14789.
Mechanistic/mammalian target of rapamycin (mTOR) is a central factor of protein synthesis signaling and plays an important role in the resistance training-induced increase in skeletal muscle mass and subsequent skeletal muscle hypertrophy response. In particular, mTOR complex 1 (mTORC1) promotes protein synthesis in ribosomes by activating the downstream effectors, p70S6K and 4EBP1, in skeletal muscle and is highly sensitive to rapamycin, an mTOR inhibitor. Recently, resistance training has also been shown to affect mitochondrial dynamics, which is coupled with mitochondrial function. In skeletal muscle, mitochondria dynamically change their morphology through repeated fusion and fission, which may be key for controlling the quality of skeletal muscle. However, how the mechanisms of mitochondrial dynamics function during hypertrophy in skeletal muscle remains unclear. The aim of this study was to examine the impact of mTOR inhibition on mitochondrial dynamics during skeletal muscle hypertrophy. Consistent with previous studies, functional overload by synergist (gastrocnemius and soleus) ablation-induced progressive hypertrophy (increase in protein synthesis and fiber cross-sectional area) of the plantaris muscle was observed in mice. Moreover, these hypertrophic responses were significantly inhibited by rapamycin administration. Fourteen days of functional overload increased levels of MFN2 and OPA1, which regulate mitochondrial fusion, whereas this enhancement was inhibited by rapamycin administration. Additionally, overload decreased the levels of DRP1, which regulates mitochondrial fission and oxidative phosphorylation, regardless of rapamycin administration. These observations suggest that the relative reduction in mitochondrial function or content is complemented by enhancement of mitochondrial fusion and that this complementary response may be regulated by mTORC1.
机械/哺乳动物雷帕霉素靶蛋白（mTOR）是蛋白质合成信号的核心因素，在阻力训练引起的骨骼肌质量增加和随后的骨骼肌肥大反应中发挥重要作用。特别是，mTOR 复合物 1（mTORC1）通过激活下游效应物 p70S6K 和 4EBP1 在骨骼肌中促进核糖体的蛋白质合成，并且对雷帕霉素（mTOR 抑制剂）高度敏感。最近，阻力训练也被证明会影响线粒体动力学，这与线粒体功能有关。在骨骼肌中，线粒体通过反复融合和裂变动态改变其形态，这可能是控制骨骼肌质量的关键。然而，mTOR 抑制在骨骼肌肥大过程中线粒体动力学的作用机制仍不清楚。本研究旨在探讨 mTOR 抑制对骨骼肌肥大中线粒体动力学的影响。与先前的研究一致，协同肌（比目鱼肌和腓肠肌）切除引起的功能超负荷导致比目鱼肌渐进性肥大（蛋白质合成和纤维横截面积增加），在小鼠中观察到。此外，雷帕霉素给药显著抑制了这些肥大反应。14 天的功能超负荷增加了调节线粒体融合的 MFN2 和 OPA1 的水平，而雷帕霉素给药抑制了这种增强。此外，无论是否给予雷帕霉素，过载都会降低调节线粒体裂变和氧化磷酸化的 DRP1 水平。这些观察结果表明，线粒体功能或含量的相对减少通过增强线粒体融合得到补充，而这种互补反应可能受 mTORC1 调节。
