Department of Orthopaedics and Traumatology, University Hospital Agostino Gemelli, Catholic University of the Sacred Heart, Rome, Italy. emarzetti @ live.com
Gerontology. 2012;58(2):99-106. doi: 10.1159/000330064. Epub 2011 Sep 23.
Sarcopenia, the age-related loss of muscle mass and function, represents a relevant public health issue due to its high prevalence and detrimental consequences. While the exact mechanisms underlying the pathogenesis of sarcopenia are not clear, growing experimental evidence indicates that progressive myonuclear elimination over the course of aging via an apoptosis-like process may represent a converging mechanism through which muscle atrophy and loss of physical function develop. Notably, the proapoptotic environment taking place in aged muscle appears amenable to interventions.
We aimed at providing (1) an overview of signaling pathways of apoptosis relevant to sarcopenia, and (2) a review of the literature supporting myocyte apoptosis as a target for interventions against muscle aging.
We summarized findings from studies focused on skeletal myocyte apoptosis as a mechanism in the development of sarcopenia and reports supporting myonuclear apoptosis as a target for interventions against age-related muscle loss.
Advanced age is associated with increased signaling through extrinsic and intrinsic apoptotic pathways in skeletal myocytes. In contrast, downregulation of myocyte apoptosis through calorie restriction, exercise training, hormonal supplementation, drugs (e.g. angiotensin-converting enzyme inhibitors, acetaminophen, antimyostatin antibodies), nutraceuticals or genetic interventions (e.g. PGC-1α overexpression) is linked with preservation of muscle integrity and improved physical performance in late life. Preliminary data also indicate that skeletal myocyte apoptotic signaling may be downregulated by compounds, such as resveratrol, with calorie restriction-mimicking properties. Whether exercise mimetics exert a similar effect has not yet been investigated.
Available evidence suggests that targeting myonuclear apoptosis might provide novel and effective therapeutic tools to combat sarcopenia. Further research is required to definitely establish if downregulating myonuclear apoptosis is effective in maintaining muscle mass and function in late life, identify the most relevant apoptotic pathway(s) to target, and determine the optimal timing for intervening.
肌肉减少症是与年龄相关的肌肉质量和功能丧失，由于其高患病率和不良后果，是一个重要的公共卫生问题。虽然肌肉减少症发病机制的确切机制尚不清楚，但越来越多的实验证据表明，衰老过程中通过类似凋亡的过程进行的进行性肌核消除可能代表一种趋同机制，通过该机制肌肉萎缩和身体功能丧失发展。值得注意的是，衰老肌肉中发生的促凋亡环境似乎可以进行干预。
我们旨在提供（1）与肌肉减少症相关的凋亡信号通路概述，以及（2）支持肌细胞凋亡作为干预肌肉衰老的靶点的文献综述。
我们总结了专注于骨骼肌细胞凋亡作为肌肉减少症发展机制的研究结果，以及支持肌核凋亡作为干预与年龄相关的肌肉丧失的靶点的报告。
高龄与骨骼肌细胞中外在和内在凋亡途径的信号转导增加有关。相比之下，通过热量限制、运动训练、激素补充、药物（如血管紧张素转换酶抑制剂、对乙酰氨基酚、抗肌生成素抗体）、营养保健品或遗传干预（如 PGC-1α 过表达）下调肌细胞凋亡与肌肉完整性的保留和晚年身体机能的改善相关。初步数据还表明，具有热量限制模拟特性的化合物（如白藜芦醇）可下调骨骼肌细胞凋亡信号转导。运动模拟物是否具有类似的作用尚未进行研究。
现有证据表明，针对肌核凋亡可能为对抗肌肉减少症提供新的有效治疗工具。需要进一步研究以确定下调肌核凋亡是否有效维持晚年的肌肉质量和功能，确定最相关的凋亡途径（s）作为靶点，并确定干预的最佳时机。
