HEART FAILURE (HF) is the final common pathway for many chronic cardiac diseases and is presently the only cardiac diagnosis continuing to increase in prevalence in the United States. Patients suffering from HF report high rates of physical disability, as defined by an inability to perform simple daily activities (43). Although the reason for their physical disability is unclear, most research has focused on aerobic exercise intolerance in these patients (23). This is logical considering that the hallmark symptom of HF is exertional dyspnea and because of the widespread use of aerobic capacity as a diagnostic tool (36). Diminished aerobic capacity, however, does not greatly limit the ability of patients to perform most daily activities (42). Instead, performance of many activities of daily living is strongly dependent on muscle strength (1, 4, 44), which is determined by the size of the muscle and its contractile properties. HF patients often experience muscle atrophy and weakness during the course of the disease, which may contribute to their physical disability. The mechanisms whereby HF alters skeletal muscle size and function, however, have not been clearly defined. The mass and function of skeletal muscle are largely dictated by its protein expression, which is determined by opposing anabolic and catabolic stimuli. Insulin-like growth factor-1 (IGF-1) is believed to be a key regulator of protein metabolism, stimulating anabolic (45) and inhibiting catabolic (51) pathways. One of the key mechanisms whereby IGF-1 mediates these effects downstream of receptor activation is through phosphorylation and activation of Akt (3). The anabolic effects of Akt are mediated, in part, through activation of mammalian target of rapamycin (mTOR) (37) and inhibition of glycogen synthase kinase-3β (GSK-3β) (9). Activation of mTOR stimulates protein translation through its effects on p70 ribosomal S6 kinase (p70 S6K) and eukaryotic translation initiation factor 4E binding protein-1 (eIF4E-BP) (15), whereas Akt-mediated phosphorylation of GSK-3β (9) stimulates protein translation (45) by diminishing its inhibitory phosphorylation of eIF2B (59). Additionally, Akt activation reduces protein breakdown via phosphorylation of forkhead box O (FOXO) transcription factors (46). In their phosphorylated form, FOXOs are excluded from the nucleus, where they would otherwise stimulate transcription of E3 ubiquitin ligases important for muscle proteolysis (46, 51). Thus IGF-1, working through the activation of Akt, promotes muscle protein anabolism through reciprocal regulation of protein synthesis and breakdown. Early studies suggested that HF reduces circulating IGF-1 levels (41), but few studies have evaluated the potential effect of these alterations on skeletal muscle. In animal models of HF, reduced skeletal muscle expression of IGF-1 was found and was related to decreased muscle fiber size (48). Moreover, administration of growth hormone (10), which stimulates muscle IGF-1 expression, or muscle-specific transgenic overexpression of IGF-1 (47) inhibits muscle atrophy and improves contractile function. In human HF, skeletal muscle IGF-1 mRNA abundance (20, 53) and protein expression (20) are reduced and are correlated with decreased muscle size (20) and myofibrillar gene expression (53). Based on these results, one might expect corresponding downregulation of signaling pathways downstream of IGF-1 receptor activation. However, the one study that has examined these downstream signaling events in humans found no effect of HF (27). In addition to the paucity of knowledge about signaling distal to receptor activation, none of these studies have accounted for the fact that HF patients have low levels of physical activity (55). Muscle use positively regulates skeletal muscle IGF-1 expression and activation of downstream signaling molecules (22, 30). Thus it is unclear whether diminished local IGF-1 expression observed in prior studies (20, 48, 53) is due to HF or is a consequence of muscle disuse that accompanies the disease. Considering these caveats, the unique effect of the HF syndrome on these variables remains undefined. The conventional wisdom is that diminished circulating IGF-1 and muscle IGF-1 expression in HF patients (20, 41, 53) promote muscle atrophy and dysfunction, but virtually no studies have evaluated signaling pathways within skeletal muscle that would translate the effect of IGF-1 on muscle size and function. Thus the primary objective of the present study was to evaluate the effect of HF on skeletal muscle IGF-1 expression and the phosphorylation status of signaling molecules downstream of IGF receptor activation. The present series of experiments focused on examining the phosphorylation status of the Akt/mTOR and Akt/GSK-3β pathways since we recently found no effect of HF on FOXO-regulated genes, atrogin and MuRF1, or markers of skeletal muscle protein breakdown (39). To examine the unique effects of HF, we recruited sedentary healthy controls to match patients for activity level and studied HF patients at least 6 mo following any hospitalization to minimize any influence of disease exacerbation or muscle disuse associated with bed rest. We hypothesized that HF would be characterized by reduced skeletal muscle IGF-1 expression and, correspondingly, altered phosphorylation of Akt, mTOR, GSK-3β, and downstream signaling molecules. Moreover, decreased IGF-1 expression and signaling molecule phosphorylation would be correlated to reduced muscle size and function.