Wanagat Jonathan, Musci Robert, Herbst Allen, Aiken Judd M
Veterans Administration Greater Los Angeles Healthcare System, Los Angeles, CA, USA.
Department of Medicine, Division of Geriatrics, UCLA, Los Angeles, CA, USA.
Adv Exp Med Biol. 2025;1478:343-363. doi: 10.1007/978-3-031-88361-3_14.
This chapter describes a molecular basis for age-induced muscle fiber loss involving the mammalian mitochondrial genome (mtDNA). Early studies of human mitochondrial myopathies, which display many phenotypes associated with muscle aging, led to the search for and subsequent discovery of similar genetic and histopathological changes in aging skeletal muscle. A diverse spectrum of mtDNA deletion mutations increase in abundance with age and clonally accumulate to high abundance within individual cells. Deletion accumulation results in a focal loss of electron transport and oxidative phosphorylation. These metabolic derangements activate apoptosis, leading to necrosis, fiber splitting, and eventual fiber loss. We have identified a number of interventions that are capable of modulating mtDNA deletion mutation frequency and the abundance of electron transport chain deficient fibers. Interestingly, in each case, the genetic and histological measures of mtDNA quality predict the lifespan effects of these interventions. We highlight the value of incorporating a geroscience view into the study of sarcopenia. The sequence of events from the deletion mutation of a single mtDNA molecule to muscle fiber death is not limited to skeletal muscle and has been observed in most other aging tissues, where these events likely contribute to cell loss.
本章描述了涉及哺乳动物线粒体基因组（mtDNA）的年龄诱导性肌纤维丢失的分子基础。对人类线粒体肌病的早期研究显示出许多与肌肉衰老相关的表型，这促使人们在衰老的骨骼肌中寻找并随后发现了类似的遗传和组织病理学变化。各种各样的mtDNA缺失突变随着年龄增长而丰度增加，并在单个细胞内克隆性积累至高丰度。缺失积累导致电子传递和氧化磷酸化的局部丧失。这些代谢紊乱激活细胞凋亡，导致坏死、纤维分裂以及最终的纤维丢失。我们已经确定了一些能够调节mtDNA缺失突变频率和电子传递链缺陷纤维丰度的干预措施。有趣的是，在每种情况下，mtDNA质量的遗传和组织学指标都能预测这些干预措施对寿命的影响。我们强调了将老年科学观点纳入少肌症研究的价值。从单个mtDNA分子的缺失突变到肌纤维死亡的一系列事件并不局限于骨骼肌，在大多数其他衰老组织中也观察到了这些事件，这些事件可能导致细胞丢失。
