Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Integrated Biomedical Sciences Graduate Program, College of Graduate Health Sciences, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Cells. 2023 Jan 7;12(2):249. doi: 10.3390/cells12020249.
Sarcopenia is a debilitating skeletal muscle disease that accelerates in the last decades of life and is characterized by marked deficits in muscle strength, mass, quality, and metabolic health. The multifactorial causes of sarcopenia have proven difficult to treat and involve a complex interplay between environmental factors and intrinsic age-associated changes. It is generally accepted that sarcopenia results in a progressive loss of skeletal muscle function that exceeds the loss of mass, indicating that while loss of muscle mass is important, loss of muscle quality is the primary defect with advanced age. Furthermore, preclinical models have suggested that aged skeletal muscle exhibits defects in cellular quality control such as the degradation of damaged mitochondria. Recent evidence suggests that a dysregulation of proteostasis, an important regulator of cellular quality control, is a significant contributor to the aging-associated declines in muscle quality, function, and mass. Although skeletal muscle mammalian target of rapamycin complex 1 (mTORC1) plays a critical role in cellular control, including skeletal muscle hypertrophy, paradoxically, sustained activation of mTORC1 recapitulates several characteristics of sarcopenia. Pharmaceutical inhibition of mTORC1 as well as caloric restriction significantly improves muscle quality in aged animals, however, the mechanisms controlling cellular proteostasis are not fully known. This information is important for developing effective therapeutic strategies that mitigate or prevent sarcopenia and associated disability. This review identifies recent and historical understanding of the molecular mechanisms of proteostasis driving age-associated muscle loss and suggests potential therapeutic interventions to slow or prevent sarcopenia.
肌肉减少症是一种使人虚弱的骨骼肌肉疾病，在生命的最后几十年中加速发展，其特征是肌肉力量、质量、品质和代谢健康明显下降。肌肉减少症的多因素病因难以治疗，涉及环境因素和内在与年龄相关的变化之间的复杂相互作用。人们普遍认为，肌肉减少症导致骨骼肌肉功能逐渐丧失，超过了质量的丧失，这表明虽然肌肉质量的丧失很重要，但随着年龄的增长，肌肉质量的丧失是主要缺陷。此外，临床前模型表明，老年骨骼肌表现出细胞质量控制的缺陷，例如受损线粒体的降解。最近的证据表明，蛋白质稳态的失调，即细胞质量控制的重要调节剂，是导致肌肉质量、功能和质量与年龄相关下降的一个重要因素。虽然哺乳动物雷帕霉素靶蛋白复合物 1（mTORC1）在包括骨骼肌肥大在内的细胞控制中发挥着关键作用，但令人费解的是，mTORC1 的持续激活再现了肌肉减少症的几个特征。mTORC1 的药物抑制和热量限制显著改善了老年动物的肌肉质量，然而，控制细胞蛋白质稳态的机制尚不完全清楚。这些信息对于开发有效的治疗策略以减轻或预防肌肉减少症和相关残疾非常重要。这篇综述确定了蛋白质稳态的分子机制对与年龄相关的肌肉丧失的最新和历史理解，并提出了潜在的治疗干预措施，以减缓或预防肌肉减少症。
