Chronic Alcohol Dysregulation of Anabolic Signaling in Skeletal Muscle of SIV-Infected Rhesus Macaques

Lsu Health Sciences Center, New Orleans LA

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Abstract

? DESCRIPTION (provided by applicant): Alcohol is the most frequently abused drug in the US, and approximately 30% of US adult residents have an alcohol use disorder (AUD) during their lives. According to a recent CDC report, the prevalence of HIV infection in the US is 1.15 million individuals. The prevalence of AUD in HIV patients is greater than the prevalence of AUD in the general population. Effective anti-retroviral therapy (ART) has significantly decreased HIV patients' progression to AIDS and has increased the life expectancy of persons living with HIV/AIDS (PLWHA); however, prolonged survival has been associated with metabolic disturbances, including lipodystrophy, insulin resistance, and metabolic syndrome. Chronic alcohol consumption has also been shown to contribute to the development of insulin resistance and lipodystrophy. To our knowledge, there have been no previous studies to investigate the impact of both CBA administration and HIV/SIV on insulin signaling. Our studies, using male rhesus macaques that are chronically administered binge alcohol (CBA) or isocaloric sucrose (SUC), have revealed that CBA administration potentiates a pro-inflammatory and pro-oxidative skeletal muscle milieu and decreases phosphatidylinositol-3-kinase (PI3K) activity and results in upregulation of protein tyrosine phosphatase 1B (PTP1B) expression in skeletal muscle at the end stage of the disease. More recent studies have revealed that CBA significantly increases abdominal fat deposition and significantly decreases circulating adiponectin levels at 11 months post-SIV infection. Furthermore, frequently sampled intravenous glucose tolerance tests in these animals show that at 11 months post-SIV, CBA macaques have a significant decrease in disposition index suggesting impaired insulin responses at target tissues, including skeletal muscle. Reports in the scientific literature and our preliminary data support the central hypothesis that CBA decreases insulin- mediated anabolic responses in skeletal muscle of SIV-infected macaques. The proposed studies to be performed as part of the training plan of the applicant will use an integrated approach to assess the following Specific Aims: 1) To test the prediction that CBA decreases insulin-mediated glucose uptake and glycogen synthesis in skeletal muscle of SIV-infected macaques and 2) To identify the site(s) of insulin signaling cascade disruption in skeletal muscle of SIV-infected macaques following CBA administration. Findings from the proposed studies will provide evidence to elucidate the underlying molecular derangements in skeletal muscle insulin signaling following combination of CBA and SIV/ART and may offer insight into therapeutic targets aimed at ameliorating metabolic dysregulation in persons living with HIV/AIDS.