Disrupted Anabolic and Catabolic Processes May Contribute to Alcohol-Accentuated SAIDS-Associated Wasting

LeCapitaine, Nicole; Wang, Zhong Q.; Dufour, Jason; Potter, Barry J.; Bagby, Gregory J.; Nelson, Steve; Cefalu, William T.; Molina, Patricia E.

doi:10.1093/infdis/jir508

Cited by 34 publications

(51 citation statements)

References 34 publications

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“…As supported by our study and other similar studies, catabolic and metabolic dysregulation are central mechanisms underlying the role of alcohol in accentuation of muscle wasting at end-stage disease in simian immunodeficiency virus (SIV)-infected animals (LeCapitaine et al, 2011, Lang et al, 2009, Molina et al, 2008). However, additional mechanisms might also contribute to loss of muscle mass resulting from chronic alcohol abuse and or HIV/AIDS.…”

Section: Introductionsupporting

confidence: 82%

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

Dodd

Simon

LeCapitaine

et al. 2014

Alcoholism Clin & Exp Res

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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.

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Section: Introductionsupporting

confidence: 82%

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

Dodd

Simon

LeCapitaine

et al. 2014

Alcoholism Clin & Exp Res

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“…Our previous studies demonstrated that CBA administration to SIVinfected macaques results in significantly accentuated skeletal muscle inflammation preceding overt manifestations of alcoholic myopathy (25). In addition, we showed accentuated skeletal muscle wasting at end-stage SIV infection (24), which we later reported is characterized by marked dysregulation of ubiquitin proteasome components, increased skeletal muscle proteasomal activity, and attenuation of anabolic pathways (21). However, the possibility that the inflammatory/oxidative milieu could impact SC function and contribute to the observed accentuated wasting in CBA-administered SIV-infected macaques had not been previously examined.…”

Section: Discussionsupporting

confidence: 53%

“…These cells are quiescent during adulthood but can enter into cell cycle upon stimulation to repair damaged muscle by proliferation, differentiation, and fusion with existing myofibers (39). Our previous studies with chronic binge alcohol (CBA)-fed, Simian immunodeficiency virus (SIV)-infected rhesus macaques have shown that chronic alcohol consumption promotes a prooxidative and proinflammatory skeletal muscle milieu in SIV-infected animals, and this is associated with accentuated wasting at end-stage SIV infection (21,24). The inflammatory environment in skeletal muscle would be expected to activate quiescent SCs to proliferate and differentiate into myotubes to compensate for enhanced skeletal muscle proteolysis (39,45).…”

mentioning

confidence: 99%

“…Subsequently, the proliferation and differentiation of SCs for repair of the damaged muscle are facilitated by a second set of macrophages that secrete anti-inflammatory cytokines (45). Our previous studies have demonstrated that CBA administration to SIV-infected male macaques results in accentuated skeletal muscle upregulation of inflammatory cytokine expression and depletion of antioxidant capacity (21) compared with that of sucrose-administered SIV-infected macaques. Those findings suggest that CBA-associated chronic skeletal muscle inflammatory/oxidative milieu impairs the regenerative capacity of SCs.…”

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confidence: 99%

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Chronic binge alcohol consumption alters myogenic gene expression and reduces in vitro myogenic differentiation potential of myoblasts from rhesus macaques

Simon

LeCapitaine

Berner

et al. 2014

American Journal of Physiology-Regulatory, Integrative and Comp

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Chronic alcohol abuse is associated with skeletal muscle myopathy. Previously, we demonstrated that chronic binge alcohol (CBA) consumption by rhesus macaques accentuates skeletal muscle wasting at end-stage of simian immunodeficiency virus (SIV) infection. A proinflammatory, prooxidative milieu and enhanced ubiquitin proteasome activity were identified as possible mechanisms leading to loss of skeletal muscle. The possibility that impaired regenerative capacity, as reflected by the ability of myoblasts derived from satellite cell (SCs) to differentiate into myotubes has not been examined. We hypothesized that the inflammation and oxidative stress in skeletal muscle from CBA animals impair the differentiation capacity of myoblasts to form new myofibers in in vitro assays. We isolated primary myoblasts from the quadriceps femoris of rhesus macaques that were administered CBA or isocaloric sucrose (SUC) for 19 mo. Proliferation and differentiation potential of cultured myoblasts were examined in vitro. Myoblasts from the CBA group had significantly reduced PAX7, MYOD1, MYOG, MYF5, and MEF2C expression. This was associated with decreased myotube formation as evidenced by Jenner-Giemsa staining and myonuclei fusion index. No significant difference in the proliferative ability, cell cycle distribution, or autophagy was detected between myoblasts isolated from CBA and SUC groups. Together, these results reflect marked dysregulation of myoblast myogenic gene expression and myotube formation, which we interpret as evidence of impaired skeletal muscle regenerative capacity in CBA-administered macaques. The contribution of this mechanism to alcoholic myopathy warrants further investigation.

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“…The detrimental impact of chronic alcohol abuse on skeletal muscle mass balance is further accentuated in diseased states. Studies from our group have demonstrated that chronic alcohol consumption markedly exacerbates the end-stage muscle wasting in a simian immunodeficiency virus-infected rhesus macaques (78), and this is the result of an inflammatory, oxidative milieu that promotes dysregulation of the ubiquitin proteasome pathway (67).…”

Section: Impact Of Alcohol On Body Compositionmentioning

confidence: 99%

Alcohol Abuse: Critical Pathophysiological Processes and Contribution to Disease Burden

et al. 2014

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Alcohol abuse; the most common and costly form of drug abuse, is a major contributing factor to many disease categories. The alcohol-attributable disease burden is closely related to the average volume of alcohol consumption, with dose-dependent relationships between amount and duration of alcohol consumption and the incidence of diabetes mellitus, hypertension, cardiovascular disease, stroke, and pneumonia. The frequent occurrence of alcohol use disorders in the adult population and the significant and widespread detrimental organ system effects highlight the importance of recognizing and further investigating the pathophysiological mechanisms underlying alcohol-induced tissue and organ injury.

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Disrupted Anabolic and Catabolic Processes May Contribute to Alcohol-Accentuated SAIDS-Associated Wasting

Abstract: These data suggest negative modulation of insulin signaling coupled with enhanced Ub-proteasome system activity may be central mechanisms underlying chronic binge alcohol-induced accentuation of SIV-associated muscle wasting.

Cited by 34 publications

References 34 publications

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

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

Chronic binge alcohol consumption alters myogenic gene expression and reduces in vitro myogenic differentiation potential of myoblasts from rhesus macaques

Alcohol Abuse: Critical Pathophysiological Processes and Contribution to Disease Burden

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