Determining the context specificity of metformin treatment on muscle mitochondria and healthspan

确定二甲双胍治疗对肌肉线粒体和健康寿命的背景特异性

• 批准号: 10462944
• 负责人: Benjamin Francis Miller
• 金额: $ 65.18万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10462944
• 关键词: Aerobic; Aerobic Exercise; Age-Months; Bioenergetics; CCRL2 gene; Chronic Disease; Clinical Trials; Complex; Disease; Drug Kinetics; Drug Prescriptions; Energy Transfer; Exercise; Free Energy; Gold; Health; In Vitro; Individual; Kinetics; Longevity; Measures; Mediating; Metabolic; Metabolic dysfunction; Metformin; Mitochondria; Modeling; Morphology; Muscle Mitochondria; NADH dehydrogenase (ubiquinone); Non-Insulin-Dependent Diabetes Mellitus; Outcome; Oxidation-Reduction; Process; Proteomics; Publishing; Rattus; Reporting; Risk; Running; Skeletal Muscle; Specificity; Stress; Testing; Thermodynamics; Time; Tissues; Work; age related; exercise training; healthspan; imaging approach; improved; improved outcome; in vivo; in vivo imaging; insulin sensitivity; interest; negative affect; novel; novel strategies; pleiotropism; response; sedentary; trait; treadmill

SUMMARY Metformin, the most widely prescribed medication for treating type 2 diabetes, is increasingly recognized for healthspan effects that resemble exercise. The beneficial effects of metformin, like aerobic exercise, appear to be mediated through an energetic and/or redox stress mechanism, raising the prospect that the two approaches could exert additive or even synergistic effects. Surprisingly, our recently published clinical trial showed that metformin inhibits the beneficial effects of aerobic exercise training (AET) on skeletal muscle mitochondrial function and whole-body insulin sensitivity. Interestingly, subjects who entered the study with the highest mitochondrial complex I supported OXPHOS function and insulin sensitivity were the most negatively affected by metformin treatment. How metformin inhibits the positive effects of AET, why this effect is most pronounced in those with the highest mitochondrial function, and how these interactions ultimately impact healthspan and lifespan are unknown. The hypothesis of this proposal is that the effects of metformin on healthspan and lifespan are context specific; beneficial in the context of low energy demand/mitochondrial capacity but detrimental in the context of high energy demand/mitochondrial capacity. To test this hypothesis, the study will leverage a rat model with divergent selection for intrinsic aerobic capacity, referred to as high capacity and low capacity runners (HCR/LCR). By selecting for maximal treadmill running capacity, LCR and HCR rats diverged in intrinsic mitochondrial function, lifespan and metabolic traits that increase or decrease risk for chronic disease. Changes in mitochondrial function will be assessed using ex vivo respirometry that measures the interplay among three thermodynamic forces. Further, the proposal uses targeted kinetic and quantitative mitochondrial proteomics to understand appropriate or aberrant cellular remodeling, and novel in vivo imaging approaches to understand changes in mitochondrial morphology and dynamics. The Specific Aims are to: 1) establish if mitochondrial changes to metformin treatment are context specific, 2) establish if the effects of metformin on adaptations to aerobic exercise training are context specific, and 3) determine whether the beneficial effects of metformin on healthspan and lifespan are context specific. It is expected that with metformin treatment, remodeling of mitochondria will be consistent with improved outcomes in LCR rats, but have no effect or will be detrimental in HCR, with or without exercise training. Further it is expected that metformin will extend healthspan and lifespan in LCR rats, but not HCR rats. Successful completion of these aims will reveal the importance of context specificity on metformin action and the mechanisms underlying its positive and potentially negative impacts on healthspan and lifespan. This information is critical given the ever expanding off-target use of metformin in healthy individuals without chronic disease and/or overt metabolic dysfunction. Results from this project will help inform who can benefit from metformin treatment, and more importantly, who should avoid it.

概括 二甲双胍是治疗2型糖尿病的最广泛规定的药物，越来越多地认可 类似于运动的HealthSpan效果。二甲双胍等有氧运动的有益作用似乎 通过能量和/或氧化还原应力机制进行介导，从而提高了这两个方法的前景 可能发挥添加剂甚至协同作用。令人惊讶的是，我们最近发表的临床试验表明 二甲双胍抑制有氧运动训练（AET）对骨骼肌线粒体的有益作用 功能和全身胰岛素敏感性。有趣的是，进入研究的受试者 线粒体复合物I支持OXPHOS功能和胰岛素敏感性是最负面影响的 通过二甲双胍治疗。二甲双胍如何抑制AET的积极作用，为什么这种效果最为明显 在线粒体功能最高的人中，这些相互作用最终如何影响健康范围和 寿命是未知的。该提议的假设是二甲双胍对HealthSpan和寿命的影响 特定于上下文；在低能需求/线粒体能力的背景下有益，但在 高能量需求/线粒体能力的背景。为了检验这一假设，该研究将利用大鼠模型 固有有氧能力的不同选择，称为高容量和低容量跑步者 （HCR/LCR）。通过选择最大的跑步机跑步能力，LCR和HCR大鼠固有的 线粒体功能，寿命和代谢特征增加或降低慢性病风险。更改 在线粒体功能中，将使用离体呼吸测定法评估三个相互作用 热力学力。此外，该提案使用靶向动力学和定量线粒体蛋白质组学 了解适当或异常的蜂窝重塑，并了解新颖的体内成像方法 线粒体形态和动力学的变化。具体目的是：1）确定是否线粒体 二甲双胍治疗的变化是特定于情境的，2）确定二甲双胍对适应的影响是否对 有氧运动训练是特定于背景的，3）确定二甲双胍的有益作用是否对 HealthSpan和寿命是特定于上下文的。预计通过二甲双胍治疗，重塑 线粒体将与LCR大鼠的预后改善一致，但无效或不会有害 HCR，有或没有运动训练。此外，预计二甲双胍将延长HealthSpan和寿命 在LCR大鼠中，但不是HCR大鼠。这些目标的成功完成将揭示上下文的重要性 对二甲双胍作用的特异性以及其积极和潜在的负面影响的机制 HealthSpan和寿命。鉴于在不断扩展的脱毛蛋白中，此信息至关重要 没有慢性疾病和/或明显代谢功能障碍的健康个体。该项目的结果将有所帮助 告知谁可以从二甲双胍治疗中受益，更重要的是，谁应该避免。