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

According to the Centers for Disease Control and Prevention, >400 000 people were living with AIDS in the United States at the end of 2003 [1]. The reduction in human immunodeficiency virus (HIV)–associated morbidity and mortality resulting from the use of highly active antiretroviral therapy (HAART) has made HIV infection a chronic disease, during which individuals are likely to engage in alcohol and drug abuse at rates comparable to those in the noninfected population [2]. Chronic alcohol consumption remains the most common and costly form of drug abuse with ∼14 million Americans fulfilling the diagnostic criteria for alcohol abuse and/or alcoholism. Indeed, alcohol abuse and HIV infection frequently co-exist [3]. Muscle wasting remains an important determinant of increased morbidity and mortality observed in AIDS [4–7]. Chronic alcohol abuse is associated with skeletal muscle myopathy [8] resulting from decreased muscle protein synthesis [9–11] and possibly accelerated muscle proteolysis [12]. Additionally, indirect effects of alcohol such as alterations in nutritional state, micronutrient availability, and growth factor expression have been implicated in the etiology of alcohol-induced muscle wasting [13]. Because loss of lean body mass has a deleterious impact on the overall survival of HIV-infected individuals, factors that accelerate this process, such as chronic alcohol consumption, likely accelerate disease progression and development of AIDS-associated wasting [14–17]. We have previously shown that chronic binge alcohol-administered SIV-infected (ALC/SIV+) macaques had significantly lower body weight, body mass index (BMI), and limb muscle area compared with sucrose-treated SIV-infected (SUC/SIV+) animals [18]. In addition, our studies showed messenger RNA (mRNA) expression of IGF-1 is suppressed, atrogin-1 is increased, TNF-α is significantly increased, and myostatin is modestly elevated in skeletal muscle from ALC/SIV+ animals at terminal stage of SIV infection (SAIDS) [18]. Atrogin-1 is a muscle-specific E3 ubiquitin ligase and has been implicated as a causal factor in muscle wasting [19]. Tumor necrosis factor α (TNF-α) has been shown to exert anti-insulin effects in skeletal muscle [20, 21], and the negative regulator of skeletal muscle growth, myostatin [22], has been implicated in muscle wasting in HIV-infected men [23]. Together, our findings suggested upregulation of the ubiquitin (Ub)–proteasome system as a predominant mechanism underlying loss of skeletal muscle mass observed in those studies. However, it was not investigated whether parallel suppression in anabolic regulatory pathways was also involved. Moreover, whether localized skeletal muscle inflammation was associated with an oxidative milieu further contributing to dysregulation in muscle mass was not investigated. The present study extends our observations to integrate the role of disrupted anabolic signaling as an additional, potentially synergistic mechanism that is responsible for disruption in the balance between the synthetic and catabolic mechanisms leading to erosion of muscle mass in chronic binge alcohol-administered SIV-infected macaques.