Mitochondrial involvement and impact in aging skeletal muscle.
Mitochondrial involvement and impact in aging skeletal muscle.
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DOI：
10.3389/fnagi.2014.00211
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发表时间：
2014
影响因子：
4.8
通讯作者：
Hepple RT
中科院分区：
文献类型：
--
作者：
Hepple RT
萎缩是衰老骨骼肌的一个明显特征，它会导致进行性虚弱，并增加高龄时行动能力障碍、摔倒和身体虚弱的风险。衰老肌肉萎缩最常见的机制之一是线粒体功能障碍。最近的研究采用了适合于研究线粒体内在功能的方法，发现在经历萎缩的衰老大鼠肌肉中，线粒体呼吸和活性氧释放的变化是不一致的，而在七十多岁的体力活动受试者的人体骨骼肌中表现为正常。另一方面，对渗透性转变的敏感性似乎是随着年龄的增长萎缩肌肉的普遍特征，这种影响甚至出现在身体活跃的七十多岁的受试者的萎缩肌肉中。除了线粒体功能的这种内在变化外，线粒体外部的因素也可能调节衰老肌肉中的线粒体功能。特别是，最近的证据表明，衰老环境中的氧化应激是抑制体内呼吸功能的一个因素(这种影响在体外是不存在的)。此外，在非常高的年龄，不仅肌肉萎缩变得更加严重，其影响在临床上也是相关的，而且有证据表明，这是由严重萎缩的失神经肌肉纤维积累所致。由于去神经支配本身可以调节线粒体的功能，并重新启动线粒体介导的萎缩途径，未来的研究需要解决超高龄骨骼肌线粒体的改变在多大程度上是去神经支配的结果，而不是初级细胞器缺陷，以完善我们对线粒体作为更高年龄治疗靶点的相关性的理解。
Atrophy is a defining feature of aging skeletal muscle that contributes to progressive weakness and an increased risk of mobility impairment, falls, and physical frailty in very advanced age. Amongst the most frequently implicated mechanisms of aging muscle atrophy is mitochondrial dysfunction. Recent studies employing methods that are well-suited to interrogating intrinsic mitochondrial function find that mitochondrial respiration and reactive oxygen species emission changes are inconsistent between aging rat muscles undergoing atrophy and appear normal in human skeletal muscle from septuagenarian physically active subjects. On the other hand, a sensitization to permeability transition seems to be a general property of atrophying muscle with aging and this effect is even seen in atrophying muscle from physically active septuagenarian subjects. In addition to this intrinsic alteration in mitochondrial function, factors extrinsic to the mitochondria may also modulate mitochondrial function in aging muscle. In particular, recent evidence implicates oxidative stress in the aging milieu as a factor that depresses respiratory function in vivo (an effect that is not present ex vivo). Furthermore, in very advanced age, not only does muscle atrophy become more severe and clinically relevant in terms of its impact, but also there is evidence that this is driven by an accumulation of severely atrophied denervated myofibers. As denervation can itself modulate mitochondrial function and recruit mitochondrial-mediated atrophy pathways, future investigations need to address the degree to which skeletal muscle mitochondrial alterations in very advanced age are a consequence of denervation, rather than a primary organelle defect, to refine our understanding of the relevance of mitochondria as a therapeutic target at this more advanced age.