PDF(Pubmed)
Abstract：
Human hallmarks of sarcopenia include muscle weakness and a blunted response to exercise. Nicotinamide N-methyltransferase inhibitors (NNMTis) increase strength and promote the regenerative capacity of aged muscle, thus offering a promising treatment for sarcopenia. Since human hallmarks of sarcopenia are recapitulated in aged (24-month-old) mice, we treated mice from 22 to 24 months of age with NNMTi, intensive exercise, or a combination of both, and compared skeletal muscle adaptations, including grip strength, longitudinal running capacity, plantarflexor peak torque, fatigue, and muscle mass, fiber type, cross-sectional area, and intramyocellular lipid (IMCL) content. Exhaustive proteome and metabolome analyses were completed to identify the molecular mechanisms underlying the measured changes in skeletal muscle pathophysiology. Remarkably, NNMTi-treated aged sedentary mice showed ~ 40% greater grip strength than sedentary controls, while aged exercised mice only showed a 20% increase relative to controls. Importantly, the grip strength improvements resulting from NNMTi treatment and exercise were additive, with NNMTi-treated exercised mice developing a 60% increase in grip strength relative to sedentary controls. NNMTi treatment also promoted quantifiable improvements in IMCL content and, in combination with exercise, significantly increased gastrocnemius fiber CSA. Detailed skeletal muscle proteome and metabolome analyses revealed unique molecular mechanisms associated with NNMTi treatment and distinct molecular mechanisms and cellular processes arising from a combination of NNMTi and exercise relative to those given a single intervention. These studies suggest that NNMTi-based drugs, either alone or combined with exercise, will be beneficial in treating sarcopenia and a wide range of age-related myopathies.
摘要：
肌肉减少症的人类标志包括肌肉无力和对运动的迟钝反应。烟酰胺N-甲基转移酶抑制剂（NNMTis）增加力量并促进衰老肌肉的再生能力，从而为肌少症提供了一种有希望的治疗方法。由于肌肉减少症的人类标志是在老年（24个月大）小鼠中概述的，我们用NNMTi治疗22至24月龄的小鼠，密集运动,或者两者的结合，并比较了骨骼肌的适应性，包括握力，纵向运行能力，足底屈肌峰值扭矩，疲劳,和肌肉质量，光纤类型,横截面积,和肌细胞内脂质(IMCL)含量。完成了详尽的蛋白质组和代谢组分析，以确定骨骼肌病理生理学测量变化的分子机制。值得注意的是,NNMTi处理的老年久坐的小鼠比久坐的对照组显示出约40％的握力。而老年运动小鼠相对于对照组仅显示20％的增加。重要的是,NNMTi治疗和运动带来的握力改善是累加的，NNMTi处理的运动小鼠相对于久坐对照的握力增加了60%。NNMTi治疗还促进了IMCL含量的可量化改善，结合锻炼，显著增加腓肠肌纤维CSA。详细的骨骼肌蛋白质组和代谢组分析揭示了与NNMTi治疗相关的独特分子机制，以及与给予单一干预的NNMTi和运动组合产生的独特分子机制和细胞过程。这些研究表明，基于NNMTi的药物，单独或结合锻炼，将有利于治疗肌肉减少症和广泛的年龄相关性肌病。
