Expression of neuromuscular junction genes in simian immunodeficiency virus infection: impact of chronic binge alcohol and antiretroviral therapy

Abstract

Of the 1.5 million people living with HIV/AIDS (PLWHA) in the United States, approximately 40% have a history of alcohol use disorders. Decreased skeletal muscle mass and function remains a strong and consistent predictor of mortality among PLWHA and occurs at an earlier age among PLWHA compared to the general population. We have previously demonstrated that chronic binge alcohol (CBA) alters gene and microRNA expression and DNA methylation of genes involved in neuromuscular junction function in skeletal muscle obtained at end‐stage of simian immunodeficiency virus (SIV) infection in male rhesus macaques. The aim of this study was to determine whether CBA and/or antiretroviral therapy (ART) altered skeletal muscle expression of genes involved in neuromuscular junction during earlier stages of SIV‐infection in male rhesus macaques. Daily CBA (blood alcohol levels ~50 mM) or sucrose (SUC) administration was initiated 3 months prior to intrarectal SIVmac251 inoculation and continued throughout the study period. Antiretroviral therapy (ART) or placebo was initiated 2.5 months after SIV infection and continued through the study period. Four treatment groups (SUC/SIV±ART and CBA/SIV±ART) were studied at endpoint (11 months post SIV‐infection). Our results demonstrate that CBA and ART decreased expression of brain derived neurotrophic factor (BDNF) in the muscle. SIV increased expression of Acetylcholine receptor gene (AChR) irrespective of CBA or SUC administration in non‐ART treated macaques. However, ART decreased AChR expression to levels similar to controls. No significant changes in the expression of Agrin, Muscle Associated Receptor Tyrosine Kinase (MuSK), Neuregulin, Low‐ Density Lipoprotein Receptor‐Related Protein 4 (LRP4) were detected. We have previously reported that CBA decreases miR‐206 and increases HDAC4 expression in the muscle, and that HDAC4 is a direct target of miR‐206. Expression of BDNF and AChR are reported to be regulated by miR‐206 and/or HDAC4. We hypothesize that the dysregulation of miR‐206‐HDAC4 axis due to CBA potentially plays a role in impairing genes involved in neuromuscular function. Future studies will determine the functional relevance of impaired neuromuscular gene expression and its potential role in compromised skeletal muscle function due to alcohol use in PLWHA.Support or Funding InformationResearch reported was supported by the National Institutes of Health under award numbers P60 AA009803, 1K01AA024494‐01A1