Pediatr Nephrol (2008) 23:527–535 41, 43–45] (Table 2). It is important to emphasize that the correction of metabolic acidosis has been shown to decrease protein breakdown in various clinical trials, indicating why maintaining normal serum bicarbonate levels should be part of standard clinical care (Table 1). The finding that various diseases with muscle wasting are caused by activation of the UPS, plus the fact that coordinated changes in the expression of genes in muscle occur in different catabolic states, suggest that catabolic states activate a common cellular signaling pathway [28]. One signaling pathway is a decrease in phosphatidylinositol 3-kinase (PI3K) activity (Fig. 2). The involvement of this signaling pathway follows from the finding that several catabolic illnesses, including sepsis, acidosis, uremia, and diabetes, are characterized by insulin resistance [41, 44, 46, 47]. In normal muscle, binding of insulin or insulin-like growth factor (IGF)-1 to their receptors increases the activities of PI3K and its downstream target, Akt. In insulin-resistant conditions or with deficiency of IGF-1, the activity of this signaling pathway is depressed [35, 48, 49]. When PI3K activity falls, there is decreased production of phosphatidylinositol-3,4,5 phosphate (PIP3), leading to decreased phosphorylation and activity of the downstream serine/threonine kinase, Akt. This is a key step, because activated Akt is a major stimulator of growth-related processes via phosphorylation of the downstream kinases, GSK1 and mTOR/S6kinase, stimulating protein synthesis. On the other hand, reduced PI3K-Akt signaling (as occurs in insulin resistance) enhances protein breakdown in muscle [41]. The rise in muscle protein losses is associated with two catalytic processes: first, caspase-3 is activated to break down the complex structure of muscle; second, there is increased expression of the E3 ubiquitin ligases, atrogin-1 and MuRF-1, to degrade the proteins made available by caspase-3 [35–37] (Fig. 2). The result is muscle wasting. Table 2 Metabolic acidosis in otherwise normal humans changed hormonal levels or responses to hormones Hormone Growth hormone (GH) [80–84] Insulin [44, 85, 86] Insulin-like growth factor (IGF)-1 [81, 84, 87] Thyroid hormone [82, 88] Glucocorticoids [89] Parathyroid hormone (PTH) [90, 91] Vitamin D [91] Acidosis-induced response Suppressed GH secretion Lower IGF-1 response Suppressed insulin-stimulated glucose metabolism Decreased IGF-1 in plasma, and kidney and liver (but not in muscle) Decreased plasma T3 and T4 levels plus a higher plasma thyroid-stimulating hormone Increased glucocorticoid production Decreased sensitivity of PTH secretion to changes in plasma calcium Suppressed activation to 1,25 (OH)2 cholecalciferol 531 Fig. 2 The balance between muscle hypertrophy and atrophy depends on whether protein synthesis is more active than degradation or vice versa. In protein synthesis, insulin-like growth factor (IGF)-1 and insulin signaling leads to increased phosphatidylinositol 3-kinase (PI3K), which promotes Akt phosphorylation (Akt-P). Akt-P pro- motes phosphorylation of GSK1 and mTOR/S6 kinases, leading to increased protein synthesis. Akt-P also phosphorylates the forkhead (FoxO) transcription factor, preventing it from entering the nucleus to promote expression of atrogin-1, MuRF-1, and other atrogenes, thereby blocking protein degradation. In protein degradation, the opposite pathway happens, but additionally, decreased Akt-P leads to increased caspase-3 activity, further promoting degradation. In inflammation, it is thought that tumor necrosis factor (TNF)-α and other inflammatory cytokines phosphorylate the inhibitor of nuclear factor (NF)-κB (IκB), to free NF-B to enter the nucleus and promote MuRF-1 expression, and ultimately, muscle protein degradation. (Reproduced with permission from [15]) How are the two mechanisms activated? In studies of muscles from insulin-deficient rats or db/db mice (a model of insulin resistance), we found that accelerated muscle protein degradation increases the level of the proapoptotic factor, Bax [35, 41]. This is relevant because activated Bax causes the release of cytochrome C from mitochondria. Cytochrome C release, in turn, activates caspase-3 to trigger actomyosin/myofibril cleavage, leaving behind the 14kD actin fragment marker [35]. The activation of atrogin-1, and hence the UPS, involves another mechanism: changes in activity of the fork-head transcription factors (FoxO 1, 3 and 4). When these transcription factors are phosphorylated by Akt, they cannot enter the nucleus to stimulate transcription of atrogin-1. However, when PI3K/Akt activ- ities are low, the FoxOs are not phosphorylated, so they can enter the nucleus to increase the transcription of atrogin-1, resulting in an increase in muscle protein degradation [35–37].