Alcohol-induced Skeletal Muscle Insulin Insensitivity in SIV/HIV: Myotube-derived Extracellular Vesicle-mediated Mechanisms

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Abstract The primary purpose of this Ruth L. Kirschstein NRSA F30 application is to provide the groundwork that will prepare the applicant for an academic medical career. Much of the applicant’s career development will come from work in High Priority HIV/AIDS comorbidity-related research, and she will have the invaluable opportunity to carry out high quality research using a well-established preclinical model of chronic binge alcohol (CBA) and simian immunodeficiency virus (SIV) infection. At-risk alcohol use is twice as likely in people living with HIV (PLWH) as it is in the general population. PLWH on antiretroviral therapy (ART) have a near normal life expectancy, but there is an increase in prevalence of metabolic comorbidities, requiring a need for research studying pathophysiological mechanisms of metabolic dysregulation in the context of HIV. Studies from our group have shown that at-risk alcohol use and CBA is associated with impaired insulin/glucose dynamics in PLWH and in SIV-infected macaques, respectively. Skeletal muscle (SKM) is a major site of insulin-dependent glucose uptake, and preclinical studies indicate that alcohol decreases SKM insulin sensitivity. Preliminary data generated for this application suggest that CBA dysregulates proteins in the insulin signaling pathway in SKM, further indicating that alcohol leads to SKM dysfunction. With previous work from our group demonstrating that CBA-mediated alterations in myotubes reflect what is seen in SKM, we will utilize cultured myotubes to reflect changes seen in SKM in our proposed experiments. Extracellular vesicles (EVs) mediate cellular changes in pathologic and therapeutic conditions by transporting bioactive cargo, including microRNAs (miRNAs), between cells. miRNAs are small non-coding RNAs that regulate gene expression and are differentially expressed by CBA and insulin resistance. Preliminary and previous data suggests that CBA leads to lower expression of the SKM specific miRNA-206 in plasma EVs and the SKM of SIV-infected macaques, and miRNA-206 is implicated in SKM insulin-dependent glucose uptake. Taken together, our preliminary data and published literature support the hypothesis, that alcohol-mediated alterations in myotube extracellular vesicle miRNA cargo contribute to decreased myotube insulin sensitivity in SIV infection. The proposed study will employ a wide variety of state-of- the-art techniques to test the hypothesis using two specific aims: (1) CBA-administration alters myotube- derived EV profile in SIV-infected macaques, and (2) myotube-derived EV miRNA cargo of CBA-administered SIV-infected macaques decreases myotube insulin sensitivity. Findings from the proposed studies will provide insight on the role of EVs in alcohol-mediated SKM insulin insensitivity in SIV infection. Additionally, the proposed project aims to illustrate the therapeutic potential of EVs in improving alcohol-mediated SKM dysfunction. With a strong mentoring team committed to developing a well-rounded physician scientist, completion of the proposed training plan in High Priority HIV/AIDS comorbidity-related research will ensure that the applicant is ready to embark on a career in academic medicine.