Abstract
BackgroundThere are more than 1 million persons living with HIV/AIDS (PLWHA) in the United States and approximately 40 % of them have a history of alcohol use disorders (AUD). Chronic heavy alcohol consumption and HIV/AIDS both result in reduced lean body mass and muscle dysfunction, increasing the incidence of comorbid conditions. Previous studies from our laboratory using rhesus macaques infected with Simian Immunodeficiency Virus (SIV) demonstrated that chronic binge alcohol (CBA) administration in the absence of antiretroviral therapy exacerbates skeletal muscle (SKM) wasting at end-stage SIV disease. The aim of this study was to characterize how CBA alters global gene regulatory networks that lead to SKM wasting at end-stage disease. Administration of intragastric alcohol or sucrose to male rhesus macaques began 3 months prior to SIV infection and continued throughout the duration of study. High-output array analysis was used to determine CBA-dependent changes in mRNA expression, miRNA expression, and promoter methylation status of SKM at end-stage disease (~10 months post-SIV) from healthy control (control), sucrose-administered, SIV-infected (SUC/SIV), and CBA-administered/SIV-infected (CBA/SIV) macaques.ResultsIn addition to previously reported effects on the extracellular matrix and the promotion of a pro-inflammatory environment, we found that CBA adversely affects gene regulatory networks that involve “universal” cellular functions, protein homeostasis, calcium and ion homeostasis, neuronal growth and signaling, and satellite cell growth and survival.ConclusionsThe results from this study provide an overview of the impact of CBA on gene regulatory networks involved in biological functions, including transcriptional and epigenetic processes, illustrating the genetic and molecular mechanisms associated with CBA-dependent SKM wasting at end-stage SIV infection.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-2329-z) contains supplementary material, which is available to authorized users.
Highlights
There are more than 1 million persons living with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) (PLWHA) in the United States and approximately 40 % of them have a history of alcohol use disorders (AUD)
Chronic binge alcohol-dependent mRNA expression changes A total of 431 genes were significantly increased and 404 genes were significantly decreased in a chronic binge alcohol (CBA)-dependent manner
Pathways associated with transcription, programmed cell death, response to stress, protein kinase cascade and others were enriched in the CBA/Simian Immunodeficiency Virus (SIV) group (Fig. 1b)
Summary
There are more than 1 million persons living with HIV/AIDS (PLWHA) in the United States and approximately 40 % of them have a history of alcohol use disorders (AUD). Chronic heavy alcohol consumption and HIV/AIDS both result in reduced lean body mass and muscle dysfunction, increasing the incidence of comorbid conditions. Previous studies from our laboratory using rhesus macaques infected with Simian Immunodeficiency Virus (SIV) demonstrated that chronic binge alcohol (CBA) administration in the absence of antiretroviral therapy exacerbates skeletal muscle (SKM) wasting at end-stage SIV disease. Our previous studies provided evidence that chronic binge alcohol (CBA) administration accentuates metabolic derangements [11, 12, 14, 15], leading to a marked decrease in SKM mass (SAIDS wasting) and dysfunctional skeletal muscle phenotype, thereby accelerating the time to end-stage disease in SIV-infected macaques [12]. Our studies provide strong evidence that CBA accelerates the loss of SKM mass and impairs regeneration potential, which we predict would decrease quality of life and increase morbidity and mortality among PLWHA
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