1602-P: Exercise Training Reverses Skeletal Muscle DRP1 Hyperactivation and Improves Respiratory Capacity in Patients with Type 2 Diabetes

Introduction: Chronic activation of DRP1 promotes mitochondrial network fragmentation and restricts skeletal muscle glucose uptake in patients with type 2 diabetes (T2D). The purpose of this study was to determine if exercise reverses hyperactivation of skeletal muscle mitochondrial fission in patients with T2D.

Methods: 24 sedentary adults (49 ± 10 years) with obesity (BMI 36 ± 6 kg/m²) and T2D (HbA_1C 7.3 ± 1.3%; 1.3 ± 1.2 glucose lowering medications) were randomized to 12 wks of exercise training (Ex; n=11) or standard care (Ctrl; n=13). Participants randomized to Ex performed supervised aerobic exercise 5 d/wk for 60 min/session at 80-85% HR_MAX. Participants underwent a 3-day inpatient stay consisting of DXA, VO_2peak, and 2-stage hyperinsulinemic-euglycemic clamp at baseline and post intervention. Skeletal muscle biopsies were obtained for Western blot, high-resolution respirometry, and ion beam scanning electron microscopy with machine learning segmentation. Relative changes from baseline were calculated, and comparisons were made with unpaired Student’s t-tests. The primary outcome was change in pDRP1^Ser616 expression.

Results: Age, sex, body weight, and diabetes status were similar at baseline (p>0.05). Ex increased VO_2peak, lean mass, and peripheral insulin sensitivity and reduced fat mass relative to Ctrl (all p<0.05). Skeletal muscle pDRP1^Ser616 was reduced in Ex (p<0.05) independent of PGC-1α and AMPK. Ex increased maximal NADH-linked OXPHOS (p<0.05) and improved succinate- and complex III-linked OXPHOS (p<0.1). Mitochondria were elongated and had reduced sphericity after Ex (p<0.001).

Conclusions: Exercise training reversed hyperactivation of skeletal muscle mitochondrial fission and improved respiratory capacity independent of biogenesis. Collectively, these data indicate that exercise improves skeletal muscle insulin sensitivity in T2D, in part, by restoring mitochondrial dynamics and networking.