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Acetylation of Adenine Nucleotide Translocase, Fuel Selection, and Metabolic Flexibility in Human Skeletal Muscle

Introduction: Healthy, resting skeletal muscle primarily oxidizes lipid, but insulin resistant muscle oxidizes carbohydrate and shows metabolic inflexibility during hyperinsulinemia. It is unclear whether fuel selection and metabolic flexibility are dependent on insulin sensitivity in skeletal muscle performing mild exercise. Research Design and Methods: Sedentary volunteers underwent a cycle exercise protocol using stepwise increments in power output (15, 30, and 45 watts) and indirect calorimetry to estimate fuel oxidation in working muscle. Euglycemic clamps, indirect calorimetry and muscle biopsies were used to measure insulin sensitivity and acetylation and content of Adenine Nucleotide Translocase 1 (ANT1), which might be involved in fuel selection via acetylation of lysine 23, which was quantified using mass spectrometry. Results: Mild exercise produced predicted rates of oxygen consumption (11-12 ml O2/min), with low and stable blood lactate, allowing use of indirect calorimetry to calculate a respiratory exchange ratio in working muscle (RERm). ANT1 acetylation varied from 0.6 to 21% (10.3 +/- 1.2%). Exercising muscle mainly oxidized carbohydrate (45 +/- 9, 62 +/- 6, and 70 +/1 5% of total at 15, 30, and 45watts). Multiple linear regression showed that RERm rose with increasing power output (P < 0.001) and was lower with greater protein content of ANT1 (P < 0.001). Insulin-stimulated glucose disposal, ANT acetylation, and VO2peak were not predictors of RERm. Conclusions: Mildly exercising muscle in sedentary people prefers to oxidize carbohydrate independent of insulin sensitivity but depending on ANT1 protein content. The ability to oxidize lipid may be regulated by higher ANT1 content due to either higher mitochondrial abundance or greater ANT content per mitochondrial mass.