Lifestyle Intervention Reduces Skeletal Muscle Dynamin‐Related Protein‐1 (Drp1) Activation in Obese Insulin Resistant Humans

Abstract

Mitochondria play a central role in cellular bioenergetics and metabolic homeostasis. Defects in mitochondrial dynamics, the processes of fission, fusion and mitochondrial autophagy, may contribute to metabolic disease including type 2 diabetes. Drp1 is a key regulator of mitochondrial fission. We hypothesized that an exercise/diet lifestyle intervention would decrease Drp1 mediated mitochondrial fission, increase fat oxidation, and contribute to increased insulin sensitivity in older (66±1 years) obese (BMI: 34.6±0.8 kg/m2) adults. Seventeen subjects performed supervised exercise for 60 min/d, 5 days/week at 80–85% of max heart rate, and were provided a eucaloric diet for 12 weeks. Insulin sensitivity was measured by hyperinsulinemic‐euglycemic clamp and fat oxidation was determined by indirect calorimetry. Skeletal muscle biopsies were obtained from the vastus lateralis muscle prior to each clamp. The lifestyle intervention increased insulin sensitivity 2.1±0.2 fold (P<0.01) and fat oxidation 1.3±0.3 fold (P<0.01). Phosphorylation of Drp1 at Ser616 was reduced (pDrp1:tDrp1: 0.58±0.14 vs 0.81±0.15, P<0.05) following the intervention. Furthermore, reductions in the pDrp1:tDrp1 ratio were negatively correlated with increases in fat oxidation (r=−0.58, P<0.05) and insulin sensitivity (rho=−0.52, P<0.05). These are the first data to suggest that lifestyle‐mediated improvements in substrate metabolism and insulin sensitivity in obese insulin resistant adults may be regulated through decreased activation of the mitochondrial fission protein Drp1.