Novel Actions of Metformin to Augment Resistance Training Adaptations in Older Ad

描述（由申请人提供）：随着年龄的增长，骨骼肌质量和力量的下降降低了生活质量，是限制老年人独立生活机会的主要因素。进行性抗阻运动训练（PRT）是增加肌肉力量和对抗衰老肌肉萎缩最有效的干预措施；然而，总的来说，肌肉对PRT的反应是迟钝的，并且在老年人中变化很大。我们的研究小组已经确定，肌肉中抗炎、选择性活化的M2巨噬细胞的丰度可以预测老年人对PRT的反应；在训练开始前，M2巨噬细胞数量最多、炎症基因表达最低的小鼠获得的质量最大。此外，在胰岛素抵抗研究中获得的肌肉活检复查显示，二甲双胍治疗增加M2巨噬细胞丰度，降低炎症细胞因子基因表达。这些令人兴奋的发现使我们提出了我们的中心假设，即辅助二甲双胍可能通过改变肌肉组织炎症环境来改善老年人对PRT的反应，从而增强驱动PRT诱导的肌纤维肥大的机制。在Aim 1中，我们将确定二甲双胍治疗与PRT联合是否能增加老年功能受限成人的骨骼肌大小和力量。参与者将被招募并随机接受安慰剂或二甲双胍治疗2周，随后进行为期14周的PRT计划，并继续接受药物/安慰剂治疗。肌肉大小和力量的增加将被量化。在目标2中，我们将确定肌肉对二甲双胍的细胞和分子反应，这些反应与改善对PRT的反应有关。肌肉活组织检查将检查肌肉巨噬细胞、炎症基因表达、合成代谢和炎症信号通路。最后，将在Aim 3中探讨二甲双胍影响肌肉对训练反应的机制，使用人类肌肉细胞培养系统模拟运动和肌肉微环境。对可能难以进行常规锻炼计划的个体进行前瞻性识别，并确定

DESCRIPTION (provided by applicant): The loss of skeletal muscle mass and strength with advancing age reduces quality of life and is a major factor limiting an elderly person's chance of living independently. Progressive resistance exercise training (PRT) is the most effective intervention identified to increase muscular strength and combat muscle atrophy of aging; however, overall the muscle response to PRT is blunted and highly variable in the elderly. Our research team has determined that the abundance of anti-inflammatory, alternatively activated M2 macrophages in muscle predicts response to PRT in the elderly; those with the highest number of M2 macrophages and lowest inflammatory gene expression prior to the start of training gained the most mass. Further, reexamination of muscle biopsies obtained in a study on insulin resistance showed that metformin treatment increased M2 macrophage abundance, and decreased inflammatory cytokine gene expression. These provocative findings have led us to our central hypothesis that adjuvant metformin may improve the responses to PRT in the elderly by altering the muscle tissue inflammatory environment, thereby enhancing mechanisms that drive PRT-induced myofiber hypertrophy. In Aim 1, we will determine if metformin treatment augments skeletal muscle size and strength gains in conjunction with PRT in older, functionally limited adults. Participants will be recruited and randomized to receive either placebo or metformin for 2 weeks followed by a 14 week PRT program with continued drug/placebo treatment. Gains in muscle size and strength will be quantified. In Aim 2, we will identify cellula and molecular responses in muscle to metformin which are associated with improved response to PRT. Muscle macrophages, inflammatory gene expression and anabolic and inflammatory signaling pathways will be examined in muscle biopsies. Finally, mechanisms underlying metformin effects on muscle response to training, using a human muscle cell culture system modeling exercise and the muscle microenvironment, will be explored in Aim 3. Prospective identification of individuals likely to be refractory to routine exercise programs, and determining the effectiveness of metformin in improving muscle growth response to PRT, may contribute to the development of an affordable, personalized approach to maintain or restore skeletal muscle mass and strength, thereby promoting longer healthspan.