The impact of HSP72 on mitochondrial function and muscle metabolism

University Of California Los Angeles, Los Angeles CA

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Abstract

PROJECT SUMMARY Heat shock proteins (HSPs) are induced in response to metabolic stress, and induction of HSP72 specifically, is critical for protection against genetic and diet-induced obesity and insulin resistance (IR) in male rodents. We previously identified HSP72 as a chaperone of the E3 ubiquitin ligase, mitochondrial quality control protein Parkin. HSP72-knockout (KO) impaired Parkin action promoting mitochondrial dysfunction, increased adiposity, muscle lipid accumulation and IR in male mice. Herein we provide preliminary evidence that female HSP72-KO mice are lean insulin sensitive and glucose tolerant compared to WT controls. Female KO mice induced Esr1/ERα to preserve metabolic homeostasis by activating a Parkin-Drp1 axis in the control mitochondrial form, function, and health. Herein, we propose two aims to test the impact of HSP72 expression on mitochondrial form and function in the context of biological sex. SPECIFIC AIM 1. We will conduct studies in conditional muscle-specific Hspa1a deletion mouse model (mHSP72KO) to determine how HSP72 regulates the E3 ubiquitin ligase Parkin and fission regulatory partner Drp1 in the control of mitochondrial remodeling and fatty acid metabolism. We will determine the phenotypic differences and molecular mechanisms underlying the sexual dimorphism in metabolism in mHSP72KO mice by leveraging large scale differential omics analyses, AAV introduction of modified targets in muscle, and advanced molecular biology approaches in genetically engineered and primary cells in culture. SPECIFIC AIM 2. Because Esr1/ERα is induced in HSP72-KO females and these mice show improved metabolic health, we will interrogate the impact of HSP72 on ERα protein turnover/autoregulation, as well as binding partner association, post-translational modifications, Esr1 promoter accessibility and transcription factor binding. Since men show a higher prevalence of T2DM compared with age-matched premenopausal women, it is important to understand the mechanisms underlying sex dimorphisms in metabolism and metabolic disease susceptibility. This research is critical for the advance of precision therapeutics required to address sex-specific differences in disease pathobiology.