Genetic Deletion Of MicroRNA-16 In Muscle Results In Impaired Insulin Sensitivity & Exercise Capacity

Abstract

Type 2 diabetes mellitus (T2DM) has become the most common metabolic disease in Western society, leading to significant health problems and financial burdens. Numerous researchers have investigated different therapeutics to target T2DM, but the underlying molecular mechanisms are still not completely understood. Our laboratory and others have demonstrated consistent downregulation of the microRNA-16 (miR-16) in skeletal muscle across human, rodent, and tissue culture models of T2DM. PURPOSE: To investigate how deletion of miR-16 gene affects insulin sensitivity and exercise capacity during insulin resistance. METHODS: 10 wildtype (WT) and 12 muscle miR-16 knockout (KO) male mice were used for this study. At 9 wks of age, bodyweight, graded exercise test (GXT), glucose tolerance test (GTT; at 0, 30, 60, and 120 min) and insulin tolerance test (ITT; at 0, 15, 30, and 60 min) were measured. At 10 wks of age, half of the mice were given high-fat diet (HFD; 45% calories from fat) to induce insulin resistance, while the remainder were fed normal chow (NC; 17% calories from fat). At 13 wks, bodyweight, GXT, GTT, and ITT were repeated to examine the effect of HFD on miR-16 KO condition. Data were analyzed by two-way ANOVA and significance was denoted at p<0.05. RESULTS: Bodyweight was increased by ~27% in WT HFD (p<0.05) and ~21% in KO HFD group (p<0.05) compared to WT NC group. Exercise capacity was decreased by ~46% in WT HFD, ~34% in KO NC, and ~153% in KO HFD group (p<0.001) compared to WT NC group. GTT area under the curve (AUC) value was ~15% greater in WT HFD (p<0.05) and ~20% greater in KO HFD group (p<0.05) compared to WT NC group. ITT curve data indicated that glucose level was ~41% greater at 15 min in KO HFD (p<0.05) compared to WT NC group. CONCLUSION: These data suggest prior observations of downregulated muscle miR-16 in human and animal models of T2DM may in part mediate impaired insulin sensitivity and exercise tolerance. Further research is warranted to elucidate molecular mechanisms of miR-16 and its potential role in insulin resistance. ACKNOWLEDGEMENTS: This study was funded by the Arkansas Bioscience Institute and American College of Sports Medicine Research Endowment Grant.