Mitochondrial Function in High-Fat Fed and Exercise-Trained Mice Unable to Induce Autophagy

Impaired mitochondrial lipid respiration is implicated in obesity-induced insulin resistance but can be enhanced with exercise training. Autophagy is involved in remodeling the mitochondrial proteome and may be required for mitochondrial and whole-body adaptations in lipid respiration. We used a diet-induced obesity model of C57BL/6J mice and investigated the requirement of autophagy for mitochondrial adaptations to 8 weeks of treadmill exercise training using transgenic mice that cannot induce autophagy with exercise (BCL) compared to wild type controls (WT, n=3-5). High fat (HF) fed mice had lower glucose tolerance at 4 weeks compared to low fat (LF, ∼35%, P<0.01), regardless of genotype. After 8 weeks of exercise, LF-BCL mice had similar glucose tolerance to LF-WT mice. However, the HF-BCL mice had lower glucose tolerance compared to HF-WT mice (∼19%, P<0.01) suggesting a blunted improvement in glucose tolerance following training in the absence of autophagy. At week 12, mitochondria were isolated from quadriceps for respirometry. Oxidative phosphorylation capacity was normalized to electron transport system capacity. Lipid supported respiration (octanoyl-carnitine) was higher in the HF mice compared to LF (∼17%, P<0.01) and the lack of autophagy activation had no effect. Glutamate-malate-succinate supported respiration was lower in BCL mice compared to WT (∼11%, P<0.05), but only on a LF diet suggesting the requirement of autophagy for improved mitochondrial function with exercise may vary between substrates. Whole body respiratory exchange ratio was measured during 24 hours of fasting and all mice shifted to lipid oxidation with no difference between diet or genotype (P = 0.11). Collectively, skeletal muscle mitochondrial lipid oxidation was greater with HF, despite glucose intolerance. The activation of autophagy with exercise was not required for mitochondrial lipid adaptations or whole body metabolic flexibility, but may be required for non-lipid substrates.