Mitochondrial Dynamic Modulation Exerts Cardiometabolic Protection in Obese Insulin-Resistant Rats.

Abstract

Obese insulin resistance impairs cardiac mitochondrial dynamics by increasing mitochondrial fission and decreasing mitochondrial fusion, leading to mitochondrial damage, myocardial cell death and cardiac dysfunction.\xa0 Therefore, inhibiting fission and promoting fusion could provide cardioprotection in this pre-diabetic condition.\xa0 We investigated the combined effects of the mitochondrial fission inhibitor (Mdivi1) and fusion promoter (M1) on cardiac function in obese insulin-resistant rats.\xa0 We hypothesized that Mdivi1 and M1 protect heart against obese insulin-resistant condition, but also there will be greater improvement using Mdivi1 and M1 as a combined treatment.\xa0 Wistar rats (n=56, male) were randomly assigned into a high-fat diet (HFD) and normal diet (ND) fed groups.\xa0 After feeding with either normal diet or high-fat diet for 12 weeks, rats in each dietary group were divided into groups to receive either the vehicle, Mdivi1 (1.2 mg/kg, i.p.), M1 (2 mg/kg, i.p.) or combined treatment for 14 days.\xa0 The cardiac function, cardiac mitochondrial function, metabolic and biochemical parameters were monitored before and after the treatment.\xa0 HFD rats developed obese insulin resistance which led to impaired dynamics, balance and function of mitochondria, increased cardiac cell apoptosis and dysfunction. \xa0Although Mdivi1, M1 and combined treatment exerted similar cardiometabolic benefits in HFD rats, the combined therapy showed a greater reduction in mitochondrial reactive oxygen species.\xa0 Mitochondrial fission inhibitor and fusion promoter exerted similar levels of cardioprotection in a pre-diabetic condition.