Skeletal muscle MIRO1 mediates insulin resistance and muscular complications in type 2 diabetes

The National Institute of Diabetes and Digestive and Kidney Diseases awarded the University of Oklahoma Health Sciences Center $100,228 on September 30, 2026, under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847) to support research training on skeletal muscle MIRO1's role in insulin resistance and type 2 diabetes complications.

The award funds an F31 fellowship supporting two specific research aims: determining whether MIRO1 (mitochondrial Rho-GTPase 1) is a causal driver of skeletal muscle insulin resistance using cellular and animal genetic models, and defining MIRO1's role in skeletal muscle function and glucose metabolism. The research addresses a gap in understanding how mitochondrial dynamics regulate peripheral tissue metabolism, as MIRO1 has been studied extensively in neurodegenerative diseases but its function in skeletal muscle remains unexplored. The central hypothesis is that MIRO1 accumulation contributes to insulin resistance and impaired muscle function through dysregulation of intracellular calcium handling.

Performance of work is at the University of Oklahoma Health Sciences Center in Oklahoma City, Oklahoma, with a period of performance extending from September 30, 2026, through September 29, 2028. The assistance type is a Project Grant, which supports basic and clinical biomedical research that improves understanding of disease mechanisms and leads to improved prevention, diagnosis, and treatment of diabetes and related conditions.

Abstract

Type 2 diabetes (T2D) affects over 500 million individuals globally, presenting a significant public health challenge. Current treatment strategies are expensive, burdensome, and fail to target the underlying molecular mechanisms of disease progression. There is a critical need to identify novel physiological regulators of T2D to support the development of more effective and individualized therapies, which is an area aligned with the mission of the national institute of diabetes and digestive and kidney diseases (niddk). Skeletal muscle is the primary site of insulin-stimulated glucose uptake, accounting for ~80% of whole-body glucose disposal. Skeletal muscle insulin resistance is a principal hallmark of T2D. However, the mechanisms linking skeletal muscle insulin resistance to impairments in glucose homeostasis and muscle function remain incompletely understood. Mitochondria play a crucial role in muscle energy metabolism, and recent evidence suggests that mitochondrial membrane dynamics are key to maintaining metabolic health. Mitochondrial RHO-gtpase 1 (MIRO1; RHOT1) is a gtpase located on the outer mitochondrial membrane involved in mitochondrial trafficking and calcium regulation. While MIRO1 has been studied extensively in neurodegenerative diseases, its role in peripheral tissues, such as skeletal muscle, is entirely unexplored. The central hypothesis of this proposal is that MIRO1 accumulation contributes to skeletal muscle insulin resistance and impaired muscle function through dysregulation of intracellular calcium handling. This F31 fellowship will support my research training as i pursue two specific aims: (1) to determine whether MIRO1 is a causal driver of insulin resistance using cellular and animal genetic models, and (2) to define the role of MIRO1 in skeletal muscle function and glucose metabolism. These studies will use cutting-edge molecular, physiological, and imaging techniques to uncover novel MIRO1- dependent mechanisms of metabolic dysfunction. Successful completion of this project will enhance our understanding of T2D pathophysiology and potentially identify MIRO1 as a new therapeutic target for skeletal muscle insulin resistance. This research will also provide me with rigorous scientific training in metabolism, mitochondrial biology, and translational approaches to disease, consistent with the goals of the niddk to support the development of the next generation of physician-scientists and biomedical researchers.