Chronic Binge Alcohol Administration Accentuates Expression of Pro‐Fibrotic and Inflammatory Genes in the Skeletal Muscle of Simian Immunodeficiency Virus–Infected Macaques

Abstract

Background Chronic binge alcohol (CBA) administration exacerbates skeletal muscle (SKM) wasting at the terminal stage of simian immunodeficiency virus (SIV) infection in rhesus macaques. This is associated with a pro-inflammatory and oxidative milieu which we have previously shown to be associated with a disrupted balance between anabolic and catabolic mechanisms. In this study, we attempted to characterize the SKM gene expression signature in CBA-administered SIV-infected macaques; using the same animals from the previous study. Methods Administration of intragastric alcohol or sucrose to male rhesus macaques began three months prior to SIV infection and continued throughout the duration of study. Gene transcriptomes of SKM excised at necropsy (~10 mo. post-SIV) from healthy naive control (Control), sucrose-administered, SIV-infected (SUC-SIV), and CBA-administered, SIV-infected (CBA-SIV) macaques were evaluated in microarray datasets. The Protein Analysis Through Evolutionary Relationships (PANTHER) classification tool was used to filter differentially regulated genes based on their predicted function into select biological processes relevant to SKM wasting which were: inflammation, extracellular matrix (ECM) remodeling, and metabolism. Results In total, 1124 genes were differentially regulated between SUC-SIV and controls, 2022 genes were differentially expressed between the CBA-SIV and controls and 836 genes were differentially expressed between CBA-SIV and SUC-SIV animals. The relevance of altered gene expression was reflected in the up-regulation of pro-inflammatory CCL-2, CCL-8, CX3CL1, SELE, HP, and TNFRS10A mRNA expression. In addition, ECM remodeling was reflected in the up-regulation of TIMP-1, MMP2 and MMP9 mRNA expression and TGF-β protein expression. In addition, hydroxyproline content and picrosirius staining reflected increased collagen deposition in the CBA-SIV muscle tissue. Conclusions The results of the study demonstrate SKM inflammation as an important underlying mechanism for muscle wasting. In addition, the study provides evidence of SKM fibrotic transformation as a factor in CBA-induced accentuation of SIV-associated muscle wasting.

Exercise mitigates the effects of hyperhomocysteinemia on adverse muscle remodeling

“…Excessive collagen deposition, which is a hallmark of muscular fibrosis, leads to increased rigidity and decreased functionality of skeletal muscle (Gillies and Lieber ; Dodd et al. ). These findings support other studies that suggest that HHcy induces skeletal muscle weakness and impaired functionality, which could clearly be caused by muscular fibrosis (Swart et al.…”

“…Indeed, this study demonstrated that the CBS+/À gastrocnemius muscle displayed a sixfold increase in skeletal muscle collagen deposition when compared to C57 controls. Excessive collagen deposition, which is a hallmark of muscular fibrosis, leads to increased rigidity and decreased functionality of skeletal muscle (Gillies and Lieber 2011;Dodd et al 2014). These findings support other studies that suggest that HHcy induces skeletal muscle weakness and impaired functionality, which could clearly be caused by muscular fibrosis (Swart et al 2013;Veeranki et al 2015).…”

Differential contribution of chronic binge alcohol and antiretroviral therapy to metabolic dysregulation in SIV-infected male macaques

“…Our previous work demonstrated that CBA administration accentuates a dysfunctional skeletal muscle phenotype, which was associated with an accelerated time to end-stage disease in non-ART-treated SIV-infected macaques (42,43). This was characterized by increased skeletal muscle proteasomal activity, attenuation of anabolic pathways, alterations in insulin signaling (35), a profibrotic milieu (17), dysregulation of gene networks that regulate muscle homeostasis (59), and altered mitochondrial function (19). Our recent work also provides evidence that CBA decreases myoblast differentiation (58) and dysregulates mitochondrial function (18) in ART-treated macaques.…”

Chronic Binge Alcohol Administration Dysregulates Hippocampal Genes Involved in Immunity and Neurogenesis in Simian Immunodeficiency Virus-Infected Macaques

“…Studies from our laboratory have demonstrated that chronic binge alcohol (CBA) administration in non-antiretroviral treated, simian immunodeficiency virus (SIV)-infected macaques increases viral load at set-point, increases muscle wasting, accelerates time to end-stage disease, and unmasks cognitive impairment as determined by an operant learning and memory task [8,9,10,11,12]. The operant learning and memory procedure required macaques to learn a sequence of lever presses daily and emit a previously learned sequence of lever presses to obtain food reinforcement.…”