Chronic Binge Alcohol and Ovariectomy Reduce Markers of Mitochondrial Biogenesis and Function in Skeletal Muscle of SIV-infected Female Macaques

Chronic hazardous alcohol use, human/simian immunodeficiency virus (HIV/SIV) infection, and ovarian hormone loss are independently associated with skeletal muscle dysfunction. Previous research from our laboratory suggests that mitochondrial dyshomeostasis is a potential critical mechanism contributing to dysfunctional skeletal muscle metabolic mass resulting from chronic binge alcohol (CBA) administration in SIV-infected macaques. Purpose The purpose of this study was to determine the effects of CBA and ovarian hormone loss on markers of mitochondrial biogenesis and function in skeletal muscle from SIV-infected, antiretroviral therapy (ART)-treated, female rhesus macaques. Methods Macaques (N=16) were administered a daily binge dose of alcohol (CBA, 13–15g/kg/week) or isovolumetric water (VEH) for three months prior to SIVmac251 infection and throughout the duration of the study. ART administration was initiated 2.5 months after SIV infection, followed by either ovariectomy (OVX) or sham (NON-OVX) surgery one month later. At study endpoint (approximately 12 months post-SIV infection), skeletal muscle tissue was analyzed for expression of genes related to mitochondrial biogenesis [peroxisome proliferator-activated receptor (PPAR)-gamma coactivator (PGC)-1α, PGC-1β, mitochondrial transcription factor A (TFAM)], and mitochondrial function [PPARα, superoxide dismutase (SOD)2, and nuclear factor (erythroid-derived 2)-like 2 (NRF2)]. Skeletal muscle tissue homogenate was analyzed for markers of oxidative stress [4-hydroxynonenal (4-HNE), thiobarbituric acid reactive substances (TBARS), total antioxidant capacity]. Results CBA significantly (p < 0.05) reduced PGC-1β mRNA expression irrespective of OVX (relative mRNA expression: VEH=0.93 ± 0.10, CBA=0.58 ± 0.04; M ± SEM). There was a significant CBA and OVX interaction for SOD2 mRNA expression, where OVX decreased SOD2 expression compared to NON-OVX in the VEH condition (VEH/NON-OVX=1.00 ± 0.27, VEH/OVX=0.44 ± 0.07) and CBA resulted in lower SOD2 expression compared to VEH irrespective of OVX (VEH=0.63 ± 0.13, CBA=0.46 ± 0.21). No significant differences were observed for PGC-1α, TFAM, PPARα, or NRF2 mRNA expression or for markers of oxidative stress. Conclusions Ovarian hormone loss and chronic hazardous alcohol administration reduced expression of select genes important for mitochondrial biogenesis and function in skeletal muscle of SIV-infected, ART-treated female rhesus macaques during the asymptomatic phase of SIV infection. Future investigations based on these results will determine the effects of CBA and OVX on expression of proteins encoded by these genes and propose possible interventions to counteract alcohol and ovarian hormone loss-mediated skeletal muscle mitochondrial dyshomeostasis. Support or Funding Information This research was supported by grants from the National Institute on Alcohol Abuse and Alcoholism, 5P60AA009803-25 and 5T32AA007577-20. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.