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

总结 二甲双胍是治疗2型糖尿病最广泛的处方药， 类似于锻炼的健康效应。二甲双胍的有益作用，如有氧运动，似乎 通过能量和/或氧化还原应激机制介导，提高了这两种方法的前景 可以产生叠加甚至协同效应。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，进入研究的受试者中， 线粒体复合物I支持OXPHOS功能，胰岛素敏感性受到的负面影响最大 二甲双胍治疗。二甲双胍如何抑制AET的积极作用，为什么这种作用最明显 在那些线粒体功能最高的人中，以及这些相互作用最终如何影响健康， 寿命未知。该建议的假设是二甲双胍对健康和寿命的影响 是环境特异性的;在低能量需求/线粒体能力的背景下是有益的，但在低能量需求/线粒体能力的背景下是有害的。 高能量需求/线粒体能力的背景下。为了验证这一假设，该研究将利用大鼠模型 对于内在有氧能力的不同选择，被称为高能力和低能力跑步者 (HCR/LCR）。通过选择最大的跑台运动能力，LCR和HCR大鼠在内在运动能力上存在差异。 线粒体功能，寿命和代谢特征，增加或减少慢性疾病的风险。变化 将使用离体呼吸测定法评估线粒体功能， 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， 了解适当的或异常的细胞重塑，以及新的体内成像方法，以了解 线粒体形态和动力学的变化。具体目的是：1）确定线粒体是否 二甲双胍治疗的变化具有背景特异性，2）确定二甲双胍是否对适应 有氧运动训练是特定环境的，3）确定二甲双胍是否对 健康寿命和寿命取决于具体情况。预计二甲双胍治疗后， 线粒体将与LCR大鼠中改善的结果一致，但对LCR大鼠没有影响或将是有害的。 HCR，有或没有运动训练。此外，预计二甲双胍将延长健康寿命和寿命 在LCR大鼠中，而不是HCR大鼠。成功地完成这些目标将揭示背景的重要性 二甲双胍作用的特异性及其对以下方面的积极和潜在负面影响的机制 健康和寿命。鉴于二甲双胍在治疗中的脱靶使用不断扩大， 没有慢性疾病和/或明显代谢功能障碍的健康个体。该项目的成果将有助于 告知谁可以从二甲双胍治疗中获益，更重要的是，谁应该避免使用二甲双胍。

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.