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

胰岛素抵抗和失控的糖尿病在退伍军人中非常常见，并导致 肌肉力量不足，导致疾病恢复和其他与疾病有关的发病率下降。的确， 与非糖尿病患者相比，糖尿病患者在大手术后恢复力量的速度更慢。这些变化 与肌肉线粒体能量产生减少有关，但控制肌肉线粒体能量的信号 糖尿病时肌肉中的线粒体代谢仍不完全清楚。我们最近展示了 胰岛素受体(IR)和IGF-1受体(IGF1R)在肌肉控制中的重叠作用 通过细胞自噬或“自噬”来维持肌肉质量的蛋白质周转，这种控制是 依赖于FoxO转录因子。此外，我们的初步研究表明，敲除 IR/IGF1R慢性和急性导致线粒体异常，可通过缺失 肌肉发达的狐狸。这项提议的目标是研究FoxO蛋白是否控制肌肉 IR降低背景下的线粒体代谢和线粒体特异性自噬，或“有丝分裂吞噬” 和IGF1R信号。为了实现这个项目的目标，我们提出了两个目标：目标1将量化有丝分裂 利用肌肉特异性诱导物在肌肉中使用mitoTimer/LAMP1-YFP和Parkin-YFP噬线虫生物传感器 IR基因敲除，IR/IGF1R基因敲除，或IR/IGF1R与FoxO1/3/4五重基因敲除小鼠配合使用 线粒体生物能量学的测量；目标2将确定转录和 肌肉中IR/IGF1R和/或FoxOS信号丢失导致的蛋白质稳态机制 线粒体复合体损伤I.我们的长期目标是了解糖尿病和糖尿病的影响 胰岛素抵抗对肌肉线粒体蛋白质周转的影响 线粒体改变可导致力量下降和糖尿病的其他并发症，这 是我们退伍军人群体中发病率和残疾的一个重要来源。

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.