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

摘要 二甲双胍是治疗2型糖尿病最广泛的处方药，越来越多地被认为是 类似于锻炼的健康范围效应。二甲双胍的有益效果，就像有氧运动一样，似乎 通过能量和/或氧化还原压力机制进行调节，增加了这两种方法 可以发挥相加甚至协同的作用。令人惊讶的是，我们最近发表的临床试验显示 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，进入研究的受试者得分最高 线粒体复合体I支持OXPHOS功能和胰岛素敏感性受到的负面影响最大 通过二甲双胍治疗。二甲双胍是如何抑制AET的积极作用的，为什么这种作用最明显 线粒体功能最高的人，以及这些相互作用最终如何影响健康寿命和 寿命是未知的。这项建议的假设是二甲双胍对健康和寿命的影响 是特定于背景的；在低能量需求/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。为了验证这一假设，这项研究将利用一只老鼠模型 对内在有氧能力的不同选择，称为高能力和低能力跑步者 (HCR/LCR)。通过选择最大跑台运动能力，LCR和HCR大鼠在内在 增加或降低慢性病风险的线粒体功能、寿命和代谢特征。变化 将使用体外呼吸测量法来评估线粒体的功能，该呼吸测量法测量三者之间的相互作用 热力学力。此外，该提案使用定向动力学和定量线粒体蛋白质组学来 了解适当或异常的细胞重塑，以及了解新的活体成像方法 线粒体形态和动力学的变化。其具体目的是：1)确定线粒体 对二甲双胍治疗的改变是特定于上下文的，2)确定二甲双胍是否对适应 有氧运动训练是特定于具体情况的，以及3)确定二甲双胍对 健康寿命和寿命因具体情况而异。预计通过二甲双胍治疗，血管重塑 线粒体与LCR大鼠改善的结果一致，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，但不在HCR大鼠中。这些目标的成功实现将揭示语境的重要性 二甲双胍作用的特异性及其积极和潜在负面影响的机制 健康寿命和寿命。鉴于二甲双胍的非靶向使用不断扩大，这一信息至关重要。 没有慢性病和/或明显代谢功能障碍的健康个体。这个项目的结果将会有所帮助 告知谁可以从二甲双胍治疗中受益，更重要的是，谁应该避免这种治疗。

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.