These authors contributed equally to this work.
Hum Mol Genet. 2013 Oct 1;22(19):3976-86. doi: 10.1093/hmg/ddt251. Epub 2013 Jun 10.
With age, muscle mass and integrity are progressively lost leaving the elderly frail, weak and unable to independently care for themselves. Defined as sarcopenia, this age-related muscle atrophy appears to be multifactorial but its definite cause is still unknown. Mitochondrial dysfunction has been implicated in this process. Using a novel transgenic mouse model of mitochondrial DNA (mtDNA) double-strand breaks (DSBs) that presents a premature aging-like phenotype, we studied the role of mtDNA damage in muscle wasting. We caused DSBs in mtDNA of adult mice using a ubiquitously expressed mitochondrial-targeted endonuclease, mito-PstI. We found that a short, transient systemic mtDNA damage led to muscle wasting and a decline in locomotor activity later in life. We found a significant decline in muscle satellite cells, which decreases the muscle's capacity to regenerate and repair during aging. This phenotype was associated with impairment in acetylcholinesterase (AChE) activity and assembly at the neuromuscular junction (NMJ), also associated with muscle aging. Our data suggests that systemic mitochondrial dysfunction plays important roles in age-related muscle wasting by preferentially affecting the myosatellite cell pool.
随着年龄的增长，肌肉质量和完整性逐渐丧失，使老年人变得虚弱、无力，无法独立照顾自己。这种与年龄相关的肌肉萎缩被定义为肌肉减少症，似乎是多因素的，但确切原因仍不清楚。线粒体功能障碍与这一过程有关。我们使用一种新型的线粒体 DNA（mtDNA）双链断裂（DSBs）的转基因小鼠模型，该模型表现出早衰样表型，研究了 mtDNA 损伤在肌肉消耗中的作用。我们使用一种普遍表达的线粒体靶向内切酶，mito-PstI，在成年小鼠的 mtDNA 中造成 DSBs。我们发现，短暂的、短暂的系统性 mtDNA 损伤导致肌肉消耗和生命后期运动活动能力下降。我们发现肌肉卫星细胞显著减少，这降低了肌肉在衰老过程中的再生和修复能力。这种表型与神经肌肉接头（NMJ）处乙酰胆碱酯酶（AChE）活性和组装的损伤有关，也与肌肉衰老有关。我们的数据表明，系统性线粒体功能障碍通过优先影响肌卫星细胞池，在与年龄相关的肌肉消耗中发挥重要作用。
