Alcohol-induced skeletal muscle dysregulation in SIV/HIV: Mitochondrial-mediated mechanisms

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Project Summary/Abstract The primary purpose of this Ruth L. Kirschstein NRSA F32 application is to enhance the postdoctoral training of a promising young alcohol researcher and to provide research training required to conduct High Priority HIV/AIDS-related research. The applicant will gain skills to conduct basic and translational research focused on alcohol-mediated metabolic complications prevalent among people living with HIV (PLWH), which directly supports a High Priority research area designated by the NIAAA Research Program on HIV/AIDS. The applicant has a strong track record of human subjects alcohol research in the field of applied exercise physiology, which she will integrate with basic preclinical research and state-of-the-art molecular techniques to develop her research niche in alcohol-induced skeletal muscle (SKM) mitochondrial dysregulation. At-risk alcohol use among PLWH is nearly twice that in the general population. Chronic at-risk alcohol use and HIV/SIV are independently associated with metabolic comorbidities including SKM dysfunction. Previous work from our laboratory using a simian model indicates that chronic binge alcohol (CBA) administration decreases oxidative enzyme activity and maximal oxygen consumption rate in asymptomatic male macaques. Preliminary data demonstrate generated for this application show that CBA reduces mRNA expression of PGC-1β and TFAM, a downstream target of PGC-1β, in SKM of CBA-administered, asymptomatic, SIV+/ART+ female rhesus macaques. PGC-1β and TFAM are essential for mitochondrial biogenesis and homeostasis. However, the CBA-induced functional changes in SKM mitochondria and the mechanism by which CBA reduces SKM mitochondrial biogenesis and function in the context of HIV is not known. Therefore, the global hypothesis of the proposed work is that decreased PGC- 1β underlies CBA-mediated decreases in mitochondrial biogenesis and function in SKM of SIV+ female rhesus macaques and that PGC-1β is a potential therapeutic target to improve mitochondrial homeostasis. We also hypothesize that at-risk alcohol consumption decreases SKM mitochondrial biogenesis and function in PLWH. The hypothesis will be systematically tested with the following specific aims: 1) Test the hypothesis that chronic alcohol decreases mitochondrial biogenesis and function in a PGC-1β dependent manner in myoblasts from SIV+ female rhesus macaques; 2) Test the hypothesis that pharmacologically promoting PGC-1 expression will rescue CBA-mediated decreases in mitochondrial biogenesis and function in myoblasts from SIV+ female rhesus macaques; and 3) Establish that findings from non-human primates translate to PLWH with at-risk alcohol use. Data generated from the proposed application will provide a more comprehensive molecular understanding of mitochondrial dysfunction in the context of HIV and alcohol and will provide a foundation for future mechanistic and translational studies. Additionally, completing the proposed research and training will support the applicant’s progression to an independent academic career in the field of alcohol-induced skeletal muscle metabolic dysregulation in PLWH.