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

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.