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

二甲双胍在旧广告中增强抗阻训练适应性的新作用

• 批准号: 8928039
• 负责人: MARCAS M BAMMAN
• 金额: $ 61.64万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8928039
• 关键词: Adjuvant; Adult; Aging; Anti-Inflammatory Agents; Anti-inflammatory; Area; Biopsy; Blinded; Cell Culture System; Clinical Research; Coculture Techniques; Conditioned Culture Media; Cytokine Gene; Development; Disabled Persons; Effectiveness; Elderly; Environment; Exercise; Gene Expression; Goals; Growth; Health; Human; Hypertrophy; In Vitro; Individual; Inflammatory; Insulin; Insulin Resistance; Intervention; Life; Mediating; Metabolic; Metformin; Modeling; Molecular; Muscle; Muscle Cells; Muscle Fibers; Muscular Atrophy; Myoblasts; Nuclear; Organ; Participant; Persons; Pharmaceutical Preparations; Phenotype; Physiological; Placebo Control; Placebos; Positioning Attribute; Quality of life; Randomized; Recruitment Activity; Refractory; Regulation; Relative (related person); Research; Resistance; Risk; Signal Pathway; Skeletal Muscle; Stretching; System; Testing; Time; Training; Training Programs; age related; cell type; combat; cost; effective intervention; frailty; glucose uptake; improved; improved functioning; in vivo; insulin sensitivity; macrophage; monocyte; muscle form; muscle hypertrophy; muscle strength; novel; prevent; programs; prospective; response; sarcopenia; satellite cell; strength training; vastus lateralis

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.

描述（由申请人提供）：随着年龄的增长，骨骼肌质量和力量的丧失会降低生活质量，这是限制老年人独立生活机会的主要因素。进行性抗性运动训练（PRT）是确定的最有效的干预措施，可增加肌肉力量并打击衰老的肌肉萎缩。但是，总体而言，对PRT的肌肉反应在老年人中被钝化且变化很大。我们的研究小组确定，肌肉中的M2巨噬细胞的丰富性可预测老年人对PRT的反应。在开始训练之前，M2巨噬细胞数量最多且炎症基因表达最低的人获得了最多的质量。此外，对胰岛素抵抗的研究中获得的肌肉活检的重新检查表明，二甲双胍治疗增加了M2巨噬细胞的丰度，并降低了炎性细胞因子基因表达。这些挑衅性的发现使我们得出了中心假设，即辅助二甲双胍可以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诱导肌纤维肥大的机制。在AIM 1中，我们将确定二甲双胍治疗是否会增加骨骼肌的大小和力量增强与较老的成年人的PRT结合。参与者将被招募并随机接受安慰剂或二甲双胍2周，然后进行14周的PRT计划，并继续药物/安慰剂治疗。肌肉大小和力量的增长将被量化。在AIM 2中，我们将确定肌肉对二甲双胍的细胞菌和分子反应，这与改善对PRT的反应有关。在肌肉活检中将检查肌肉巨噬细胞，炎症基因表达以及合成代谢和炎症信号通路。最后，使用人类肌肉细胞培养系统建模锻炼和肌肉微环境对二甲双胍对肌肉反应的影响的机制将在AIM 3中进行探索。预期识别可能对常规锻炼程序难治的个人，并确定 二甲双胍在改善肌肉生长对PRT的反应方面的有效性，可能有助于开发负担得起的个性化方法，以维持或恢复骨骼肌质量和力量，从而促进更长的HealthSpan。