Therapeutic Potential of Extracellular Vesicles to Restore Alcohol-mediated Impairment of Myoblast Differentiation

Abstract

At-risk alcohol use in people living with HIV (PLWH) and chronic binge alcohol (CBA) administration in simian immunodeficiency virus (SIV)-infected macaques are associated with dysfunctional skeletal muscle mass. Our studies have shown that decreased myomiR-206 expression in skeletal muscle and myoblasts isolated from CBA/SIV macaques contributes to decreased myoblast differentiation. miRs transported in extracellular vesicles (EVs) mediate numerous cellular responses through intercellular communication. This study tested the hypothesis that delivery of miR-206 in EVs would ameliorate CBA-mediated decreased myoblast differentiation. Eight female rhesus macaques received either (CBA, 2.5g/kg/day) or water (VEH) for 14.5 months. Three months following the initiation of CBA/VEH, animals were infected with SIVmac251 and initiated on antiretroviral therapy 2.5 months later. Myoblasts were isolated from the vastus lateralis muscle at study endpoint (blood alcohol concentration= 0 mM) from each animal and used for ex vivo experiments including measuring differentiation, transfecting with a miR-206 mimic, and isolating EVs from myotube culture supernatant via ultracentrifugation. Myoblast differentiation measured by fusion index was lower in CBA myotubes compared to VEH (p<0.05). CBA decreased myotube-derived EV miR-206 expression (p<0.01). Transfection of myoblasts isolated from the CBA group with a mir-206 mimic increased myotube fusion index (p<0.05). Moreover, delivery of exogenous miR-206 in plasma-derived EVs increased myotube expression of miR-206 by over 450-fold (p<0.001) and significantly improved myoblast differentiation as measured by fusion index and myotube density (p<0.05). These results provide evidence that delivering miR-206 through EVs can increase CBA-mediated SKM stem cell differentiation. We propose these findings support the possible use of autologous plasma EVs as therapeutical vehicles devoid of the known adverse effects of synthetic cargo nanocarriers. Supported by: NIH/NIAAA P60AA009803, F30AA029358, K01AA024494. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.