Chronic alcohol ingestion exacerbates skeletal muscle myopathy in HIV-1 transgenic rats

Abstract

BackgroundSeparately, chronic alcohol ingestion and HIV-1 infection are associated with severe skeletal muscle derangements, including atrophy and wasting, weakness, and fatigue. One prospective cohort study reported that 41% of HIV-infected patients met the criteria for alcoholism, however; few reports exist on the co-morbid effects of these two disease processes on skeletal muscle homeostasis. Thus, we analyzed the atrophic effects of chronic alcohol ingestion in HIV-1 transgenic rats and identified alterations to several catabolic and anabolic factors.FindingsRelative plantaris mass, total protein content, and fiber cross-sectional area were reduced in each experimental group compared to healthy, control-fed rats. Alcohol abuse further reduced plantaris fiber area in HIV-1 transgenic rats. Consistent with previous reports, gene levels of myostatin and its receptor activin IIB were not increased in HIV-1 transgenic rat muscle. However, myostatin and activin IIB were induced in healthy and HIV-1 transgenic rats fed alcohol for 12 weeks. Catabolic signaling factors such as TGFβ1, TNFα, and phospho-p38/total-p38 were increased in all groups compared to controls. There was no effect on IL-6, leukemia inhibitory factor (LIF), cardiotrophin-1 (CT-1), or ciliary neurotrophic factor (CNTF) in control-fed, transgenic rats. However, the co-morbidity of chronic alcohol abuse and HIV-1-related protein expression decreased expression of the two anabolic factors, CT-1 and CNTF.ConclusionsConsistent with previous reports, alcohol abuse accentuated skeletal muscle atrophy in an animal model of HIV/AIDS. While some catabolic pathways known to drive alcoholic or HIV-1-associated myopathies were also elevated in this co-morbid model (e.g., TGFβ1), consistent expression patterns were not apparent. Thus, specific alterations to signaling mechanisms such as the induction of the myostatin/activin IIB system or reductions in growth factor signaling via CT-1- and CNTF-dependent mechanisms may play larger roles in the regulation of muscle mass in alcoholic, HIV-1 models.

Biomedical Consequences of Alcohol Use Disorders in the HIV-Infected Host

“…Moreover, we have demonstrated a strong association between the development of SAIDS wasting and decreased time to end-stage disease (from ~900 days in sucrose-fed SIV-infected to 390 days in chronic alcohol-fed SIV-infected macaques) [20]. Similar accentuation of muscle atrophy has been reported in chronic alcohol-fed HIV-1 transgenic rats [50, 51]. …”

“…Similar derangements in growth factors and proinflammatory cytokine expression have been associated with wasting in AIDS patients [74, 75], as well as in other animal models of chronic alcohol feeding and HIV infection [51, 76, 77]. Proinflammatory cytokines including IL-6 and TNF-α have been determined to exert anti-insulin effects in both skeletal muscle and adipose tissue [78, 79].…”

Aging accentuates alcohol-induced decrease in protein synthesis in gastrocnemius

“…Excess production of proinflammatory cytokines can decrease muscle protein synthesis (24), and an increase in muscle TNF-␣ and IL-6 mRNA is observed in some (8,66) but not other studies (62) in response to chronic alcohol feeding. Our current data confirm alcohol-fed rats have a selective increase in TNF-␣ and IL-6 mRNA in gastrocnemius, but no detectable change in IL-1␤ or NOS2.…”

The HIV-1 transgenic rat model of neuroHIV

“…In addition to behavioral changes, Clary et al (2011) found that, in HIV-1Tg rats, chronic alcohol consumption accentuates skeletal muscle atrophy and decreases expression of anabolic factors, CT-1 and CNTF, indicaing that alterations in these signaling mechanisms may be involved in the loss of muscle mass associated with alcoholism, especially in HIV-infected populations (Clary, Guidot et al 2011). …”