Year: 2026
Type: article
Abstract: Imbalanced skeletal muscle mitochondrial dynamics contributed to the onset and progression of type 2 diabetes (T2D) by mechanisms that remained incompletely understood. Here, we examined the role of mitochondrial Rho GTPase 1 (Miro1), an outer mitochondrial membrane enzyme, in the regulation of skeletal muscle insulin action and glucose homeostasis in T2D. Miro1 accumulated in the skeletal muscle of mice and humans with obesity and T2D, a phenomenon driven by impaired insulin-mediated interaction between AKT and Miro1 at the outer mitochondrial membrane. To determine whether Miro1 accumulation was reversible and functionally linked to metabolic improvements, we prospectively evaluated the impact of exercise training on skeletal muscle Miro1 expression, mitochondrial function, and insulin sensitivity in patients with T2D. Patients with T2D (N=24) were randomized to 12 weeks of standard care or exercise training. At baseline and after 12 weeks, we assessed changes in whole-body metabolic and mitochondrial function. Exercise training reduced skeletal muscle Miro1 accumulation (64.3% vs. -53.2% change from baseline; p=0.001) and enhanced mitochondrial oxidative capacity (-37.7% vs. 216.3% change from baseline; p=0.005) and insulin sensitivity (-18.5% vs. 80.0% change from baseline; p=0.007). To further establish a causal role for Miro1 in glucose homeostasis, we generated muscle-specific Miro1 loss- of-function models in mice and cells. Muscle-specific deletion of Miro1 improved insulin action and oxidative capacity in both models. Taken together, these findings supported a key regulatory role for skeletal muscle Miro1 in the pathophysiology of T2D.
Source: Nature Communications
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: Cleveland Clinic, University of Oklahoma, Louisiana Clinical and Translational Science Center, National Institutes of Health, National Institute on Aging, National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Complementary and Integrative Health
Awards: G1260935259, G1340642720, The Role of Nuclear Factor Erythroid 2-related factor 2 in Sarcopenic Obesity, G3667826151, G3892861298, G5850863802, Individual Differences in Obstructive Sleep Apnea, Botanical Approaches to Combat Metabolic Syndrome, Individualized Nutrition to Help Asthmatics Improve Lung Function and Energetics (INHALE), G9000035723, Hepatic SLC25a25 in Steatotic Liver Disease Progression, Metabolic Basis of Disease - Phase 2, Louisiana Clinical and Translational Science Center, Development and Regulation of the Muscle Mitochondrial Reticulum, Pennington/Louisiana NORC, Role and Regulation of Skeletal Muscle Mitochondrial Dynamics in Type 2 Diabetes, The Role of Nuclear Factor Erythroid 2-related factor 2 in Sarcopenic Obesity
OpenAlex ID: W7222914465