Preserving muscle mass and function in bedridden older adults

描述（由申请人提供）：老年人卧床休息期间肌肉质量和功能的丧失是由于肌肉蛋白质代谢调节缺陷造成的，包括对混合营养餐产生合成代谢反应的能力受损。我们建议，低强度运动和每日膳食补充亮氨酸将独立并协同地减少不活动对骨骼肌的有害影响，并促进康复过程中的恢复。代谢测量将包括： a) 营养和运动特异性翻译起始标记； b) 骨骼肌蛋白质合成； c) 一种新型的葡萄糖耐量呼气测试。形态和功能测量将包括： a) 肌肉质量和身体成分； b) 肌肉力量和功能； c) 运动激活。我们将在老年男性和女性（65-80 岁）的 7 天卧床休息和 7 天住院康复期间测试以下假设： 1. 不活动引起的代谢失调会减弱对膳食的合成代谢反应，促进瘦肌肉质量、葡萄糖耐量和功能能力的损失，而这些在康复过程中会部分恢复。 2. 在每日膳食中补充亮氨酸将维持营养刺激的翻译起始并保持对膳食摄入的合成代谢反应。这将在卧床休息期间部分保留瘦肌肉质量和功能，并促进康复期间功能和代谢能力的恢复。 3. 每日低强度运动将保持运动单位的激活，刺激运动调节的信号通路并使对膳食摄入的合成代谢反应正常化。这将在卧床休息期间部分保留葡萄糖耐量、瘦肌肉质量和功能，并促进康复。 4. 补充亮氨酸的膳食与低强度运动相结合将比单独的任何一种干预措施更有效，可以在卧床休息期间保持糖耐量、瘦肌肉质量和功能，并促进康复期间功能和代谢能力的更大提高。该转化项目将为减少身体活动不足的负面后果并促进衰老肌肉康复的策略提供机械和实用的见解。我们新颖的微创临床干预措施可直接应用于面临肌肉加速损失和功能能力下降风险的老年住院患者。

DESCRIPTION (provided by applicant): The loss of muscle mass and function in older adults during bed rest is facilitated by defects in the regulation of muscle protein metabolism, including an impaired ability to mount an anabolic response to a mixed nutrient meal. We propose that low-intensity exercise and supplementing daily meals with leucine will independently and synergistically reduce the deleterious effects of inactivity on skeletal muscle and facilitate recovery during rehabilitation. Metabolic measures will include: a) nutrient and exercise-specific markers of translation initiation; b) skeletal muscle protein synthesis; and c) a novel breath test of glucose tolerance. Morphologic and functional measures will include: a) muscle mass and body composition; b) muscle strength and function; and c) motor activation. We will test the following hypotheses in older men and women (65-80 years) during 7 days of bed rest followed by 7 days of inpatient rehabilitation: 1. Inactivity-induced metabolic dysregulation will blunt the anabolic response to meals, facilitating a loss of lean muscle mass, glucose tolerance and functional capacity that is partially restored during rehabilitation. 2. Supplementing daily meals with leucine will maintain nutrient-stimulated translation initiation and preserve the anabolic response to meal ingestion. This will partially preserve lean muscle mass and function during bed rest and facilitate the recovery of functional and metabolic capacity during rehabilitation. 3. Daily low-intensity exercise will preserve motor unit activation, stimulate the exercise-regulated signaling pathway and normalize the anabolic response to meal ingestion. This will partially preserve glucose tolerance, lean muscle mass and function during bed rest and facilitate rehabilitation. 4. Leucine-supplemented meals combined with low-intensity exercise will be a more effective stimulus than either intervention alone, preserving glucose tolerance, lean muscle mass and function during bed rest and facilitating a greater increase in functional and metabolic capacity during rehabilitation. This translational project will provide mechanistic and practical insight into strategies to reduce the negative consequences of physical inactivity and promote rehabilitation in aging muscle. Our novel, minimally invasive and clinically interventions have direct application for older hospitalized patients at risk of accelerated muscle loss and diminished functional capacity.