Regulation of Muscle Mitochondrial Protein Homeostasis by Insulin/IGF-1/FoxO Signaling

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Insulin resistance and uncontrolled diabetes are very common among Veterans and lead to decreased muscle strength, contributing to impaired recovery from illness and other disease-related morbidity. Indeed, patients with diabetes recover strength slower after major surgery than non-diabetic patients. These changes are associated with decreased muscle mitochondrial energy production, but the signals that control mitochondrial metabolism in muscle during diabetes remain incompletely understood. We recently showed that insulin receptors (IR) and IGF-1 receptors (IGF1R) display overlapping roles in the control of muscle protein turnover through cellular autophagy, or “self-eating”, to maintain muscle mass, and that this control is dependent on FoxO transcription factors. Furthermore, our preliminary studies show that knockout of IR/IGF1R both chronically and acutely lead to mitochondrial abnormalities that can be prevented by deletion of FoxOs in muscle. The goal of this proposal is to investigate whether FoxO proteins control muscle mitochondrial metabolism and mitochondrial-specific autophagy, or “mitophagy”, in the context of decreased IR and IGF1R signaling. To accomplish the goals of this project we propose 2 aims: Aim 1 will quantify mitophagy using mitoTIMER/LAMP1-YFP and Parkin-YFP mitophagy biosensors in muscle from muscle-specific inducible IR knockout, both IR/IGF1R knockout, or IR/IGF1R with FoxO1/3/4 quintuple knockout mice in concert with measurements of mitochondrial bioenergetics; Aim 2 will determine the regulation of transcriptional and protein homeostatic mechanisms by which loss of IR/IGF1R and/or FoxOs signaling in muscle leads to impairment of mitochondrial Complex I. Our long-term goals are to understand the impact of diabetes and insulin resistance on mitochondrial protein turnover in muscle to gain insights into the metabolic and mitochondrial changes that can contribute to decreased strength and other complications of diabetes, which are a significant source of morbidity and disability in our Veteran population.