Amplifying muscle and metabolic recovery in aging using metformin and leucine

Laye摘要 老年人容易出现肌肉停用的时期(手术、疾病、受伤)，导致肌肉萎缩、虚弱 和胰岛素抵抗。此外，老年人在停用事件后的肌肉和新陈代谢恢复会受到损害 成年人因此将这一弱势群体置于跌倒、骨折、住院和发展为 代谢紊乱，如2型糖尿病。一种独特的过程，可能会损害肌肉再生和 体力活动恢复过程中的葡萄糖稳态是炎症介导的脂质堆积 中间体、神经酰胺和线粒体功能降低(定义为过氧化氢释放和 线粒体生物发生)。二甲双胍是一种广泛用于成人T2D的治疗方法，具有多器官效应 包括骨骼肌，目前正在探索作为一种治疗年龄相关疾病的药物。 有趣的是，在肥胖的情况下，二甲双胍的代谢紊乱和脂肪堆积被逆转 与支链氨基酸亮氨酸(一种已知的肌肉蛋白质合成刺激剂)结合，但它是 目前尚不清楚这种治疗组合是否能增强衰老过程中停用后的肌肉和代谢恢复。 因此，这个项目的目标是重新调整二甲双胍的用途，并将其与亮氨酸结合以增加肌肉尺寸 以及老年小鼠从废用中恢复(即后肢卸载)过程中的血糖调节。此信息将 在开发新的治疗方法方面至关重要，以及时和完全扭转肌肉萎缩、虚弱和 老年人在停用后的新陈代谢下降。

Lay Abstract Older adults are prone to periods of muscle disuse (surgery, illness, injury) resulting in muscle atrophy, weakness and insulin resistance. Moreover, muscle and metabolic recovery following a disuse event is impaired in older adults thereby placing this vulnerable population at risk for falls, fractures, hospitalizations and development of metabolic disorders such as type 2 diabetes mellitus. A unique process that may impair muscle regrowth and glucose homeostasis during recovery from physical inactivity is inflammation-mediated accumulation of the lipid intermediate, ceramide, and reduced mitochondrial function (defined as H2O2 emission and decline in mitochondrial biogenesis). Metformin, a widely used treatment in adults with T2D, has multi-organ effects including skeletal muscle, and is currently being explored as a remedy to offset age-related diseases. Interestingly, metabolic disruption and lipid accumulation is reversed in conditions of obesity when metformin is combined with the branched-chain amino acid, leucine, (a known stimulant of muscle protein synthesis) but it is not known if this therapeutic combination can amplify muscle and metabolic recovery following disuse in aging. Therefore, the goal of this project is to re-purpose metformin and combine it with leucine to enhance muscle size and glucose regulation in old mice during recovery from disuse (i.e., hindlimb unloading). This information will be critical in the development new therapeutics to timely and fully reverse muscle atrophy, weakness and metabolic decline in older adults following disuse.