Role of dynamin-related protein 1 in the regulation of metabolism and skeletal muscle mass

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ABSTRACT Metabolic dysfunction, manifested clinically as the metabolic syndrome (MetSyn), is a significant health crisis in the US due to its high incidence and strong associations with obesity and type 2 diabetes. Mitochondrial dysfunction is a robust molecular underpinning contributing to key aspects of the MetSyn. My laboratory is keenly interested in the role that architecture remodeling plays in regulating mitochondrial function and cellular insulin action. Mitochondrial remodeling is achieved by fission-fusion dynamics, and impairment of these processes have been implicated in the pathobiology of metabolic disease and muscle wasting during aging. However, the molecular links between mitochondrial remodeling muscle metabolism and muscle mass are inadequately understood. We have previously shown the mitochondrial fission incompetence mediated by impaired Drp1 signaling underlies derangements in metabolism and insulin resistance. Herein we show that skeletal muscle-specific knockout of the mitochondrial fission regulator Dynamin-Related Protein 1 (Drp1) reproduces features of the MetSyn, including glucose intolerance, fat accumulation, and insulin resistance. We provide evidence that Drp1 colocalizes with succinate dehydrogenase complex assembly factor 2 (Sdhaf2) to control oxidative metabolism. Moreover, we observed a unique and dramatic muscle wasting phenotype along with mitochondrial DNA (mtDNA) depletion in the inducible Drp1 knockout mouse model. I hypothesize that Drp1 is essential for the maintenance of muscle metabolic function and mtDNA stability in part by its actions on succinate dehydrogenase (SDH)/mitochondrial complex II. This hypothesis will be tested using both constitutive and conditional muscle-specific Drp1 deletion mice: mDrp1HET and miDrp1KO. In Aim 1, both cellular and animal studies will be employed to investigate the effects of Drp1 deletion on mitochondrial function, muscle metabolism, and insulin sensitivity. In Aim 2, we will determine the role of Drp1 in the regulation of SDH/complex II activity. In Aim 3, we will determine the mechanisms of Drp1 in regulating skeletal muscle mtDNA copy number and muscle mass. These proposed studies are of important translational relevance as the research will elucidate the molecular mechanisms underlying mitochondrial dysfunction in skeletal muscle and link defective mitochondrial dynamics with features of MetSyn and type 2 diabetes mellitus-associated myopathy.