Exercise training decreases activation of the mitochondrial fission protein dynamin-related protein-1 in insulin-resistant human skeletal muscle

Abstract

Defects in mitochondrial dynamics, the processes of fission, fusion, and mitochondrial autophagy, may contribute to metabolic disease including type 2 diabetes. Dynamin-related protein-1 (Drp1) is a GTPase protein that plays a central role in mitochondrial fission. We hypothesized that aerobic exercise training would decrease Drp1 Ser(616) phosphorylation and increase fat oxidation and insulin sensitivity in obese (body mass index: 34.6 ± 0.8 kg/m(2)) insulin-resistant adults. Seventeen subjects performed supervised exercise for 60 min/day, 5 days/wk at 80-85% of maximal heart rate for 12 wk. 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 before and after the 12-wk program. The exercise 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 Ser(616) was decreased (pre vs. post: 0.81 ± 0.15 vs. 0.58 ± 0.14 arbitrary units; P < 0.05) following the intervention. Furthermore, reductions in Drp1 Ser(616) phosphorylation were negatively correlated with increases in fat oxidation (r = -0.58; P < 0.05) and insulin sensitivity (rho = -0.52; P < 0.05). We also examined expression of genes related to mitochondrial dynamics. Dynamin1-like protein (DNM1L; P < 0.01), the gene that codes for Drp1, and Optic atrophy 1 (OPA1; P = 0.05) were significantly upregulated following the intervention, while there was a trend towards an increase in expression of both mitofusin protein MFN1 (P = 0.08) and MFN2 (P = 0.07). 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.

Mitochondrial dynamics, quality control and miRNA regulation in skeletal muscle: implications for obesity and related metabolic disease

“…Furthermore, following a 12-week aerobic training intervention, a decrease in the phosphorylated (active) form of Drp-1 and an increase in Opa1 levels were reported in skeletal muscle from obese subjects with type 2 diabetes [23]. In addition, both whole-body fat oxidation, assessed by indirect calorimetry, and insulin sensitivity negatively correlated with the change of Drp-1 phosphorylation [23].…”

The therapeutic potential of metabolic hormones in the treatment of age-related cognitive decline and Alzheimer's disease

“…Aging and lifestyle factors such as diet and exercise have a substantial influence over metabolic function and metabolic hormone production [28,30,38]. Age and lifestyle-related changes in metabolism are often a result of increases in OS and inflammation [24,30,41,44], but aberrant hormone production and signaling also result in further OS and inflammation in a feed-forward fashion (Fig.…”

“…As such, PRAM has emerged as a promising alternative in replacing the native therapeutic function of human amylin and thus the treatment of both metabolic and cognitive disease [64,157–160]. Regardless of hormone intervention, proper diet and exercise can drastically improve cardiovascular health, insulin sensitivity, and the lean mass/fat mass ratio [6,38,67] and thus reduce the risk of developing both metabolic and cognitive diseases. A great deal of controversy still exists with regard to various diets and their efficacy in reducing fat mass.…”

“…Similarly, excessive amylin signaling is associated with increased ROS production, which further facilitates OS, apoptosis, and decreased insulin production within the pancreas [36,37]. This OS facilitates hormone resistance [32,38] and diffuse cellular dysfunction both centrally and peripherally [39,40]. As such, the relationship between OS and hormone resistance is highly dynamic: hormone resistance gives rise to OS, but OS can also contribute to the initial or further hormone resistance.…”

“…This change in mitochondrial morphology has been attributed to mitochondrial fragmentation, impaired ATP production, and increased OS [81]. These downstream insulin-induced changes in mitochondrial function and morphology ultimately lead to impaired glucose uptake and OS [38]; this aspect has been validated in vivo, where obese adults subjected to exercise training show increased insulin sensitivity and decreased mitochondrial fragmentation in skeletal muscle.…”