532 The influence of Akt on the other E3 ubiquitin ligase involved in muscle proteolysis, MuRF-1, is not as clearly established, and it may be linked to inflammation, as activation of NF-κB will cause overproduction of MuRF1 and muscle atrophy [37]. Besides acidosis and depressed insulin/IGF-1 action, another complication of CKD that participates in muscle wasting is increased glucocorticoid production. The com- plexity of these interactions is great because increased glucocorticoids can cause insulin insensitivity [32, 41, 50], and both insulin deficiency and insulin resistance increase glucocorticoid production. Glucocorticoids exert a permis- sive effect on protein degradation in muscle caused by several catabolic conditions. For example, activation of muscle protein breakdown does not occur in adrenalecto- mized animals with metabolic acidosis or with acute diabetes unless the animals are also given a physiological dose of glucocorticoids [32, 51–53]. Similarly, the increase in muscle proteolysis induced by Ang II or sepsis is largely eliminated by inhibiting the glucocorticoid receptor [7, 54]. This response to glucocorticoids is “permissive” because the same physiological level of glucocorticoids does not stimulate muscle protein degradation unless the animals are either acidotic or insulin deficient. These complex inter- actions actually make “physiological sense” because glu- cocorticoids evolved to integrate stress responses in different tissues. When glucose is needed, glucocorticoids mobilize amino acids from muscle protein. At the same time, glucocorticoids induce gluconeogenic enzymes in liver to catalyze the conversion of the amino acids to glucose and urea. In children, accelerated loss of protein stores associated with glucocorticoid therapy frequently results in impaired linear growth. One glucocorticoid-dependent mechanism causing these defects is impaired response to insulin (insulin insensitivity). An allied mechanism is impaired response to IGF-1 arising from decreased or impaired action of growth hormone. Indeed, administration of growth hormone has been shown to improve linear growth of children being treated chronically with glucocorticoids [55]. Moreover, growth hormone has been shown to improve growth of children with chronic catabolic diseases such as CKD; whereas growth hormone improves growth, it does not improve growth in children to (or close to) a normal height for age [56–58]. The impaired response is likely due to the multiple complications of CKD, resulting in retarded growth. Interestingly, there is a small uncon- trolled study of five children who were being treated with chronic intermittent hemodialysis and growth hor- mone. The children were then placed on an intensified daily hemodialysis regimen (3 h/day, five to six times a week) for a median time of 1.5 years [59]. The new regimen led to significant catchup growth into the range of Pediatr Nephrol (2008) 23:527–535 a normal height for age. Intensified dialysis plus growth hormone could correct acidosis, improve insulin and IGF-1 signaling and responses to other hormones, and remove unidentified uremic toxins. These responses emphasize the complexity of sorting out mechanisms for muscle wasting in CKD. Another catabolic factor associated with CKD is Ang II. Infusion of Ang II into rodents causes both anorexia and muscle protein loss by mechanisms that depend on glucocorticoids [7]. Also, there is the knotty problem of understanding the influence of inflammation. In this case, the mechanism(s) causing muscle wasting in inflammation is not clear. Suggested responses include the ability of certain inflammatory mediators to cause insulin resistance, as well as a more direct influence of inflammatory mediators on muscle protein metabolism (Fig. 2). The problem is difficult because the link between an increase in inflammatory markers in uremic patients (e.g. C-reactive protein) to loss of muscle mass has not been established [60, 61]. Finally, there is an intriguing protein—myostatin—a member of the transforming growth factor (TGF)-β family of cytokines. It is produced in skeletal and cardiac muscle and regulates muscle growth by limiting it [62]. Overexpression of myostatin in muscle leads to loss of protein mass via inhibition of Akt phosphorylation with an increase in active FoxO1; this increases the expression of atrophy-related genes [63, 64]. Underexpression of myo- statin results in skeletal muscle hypertrophy [65]. An increase in myostatin expression is found in several cachexia-associated disease states. However, there is limited information about the influence of kidney disease on myostatin expression and function beyond changes in myostatin mRNA [66, 67]. Conclusion In this brief review of mechanisms causing muscle protein losses, we discussed how a complex series of biochemical reactions are coordinated to create a genetic program that degrades muscle proteins. We also identified an initial step in muscle proteolysis that leaves behind a biomarker in muscle, the 14kD actin fragment, resulting from caspase-3. We emphasized how the UPS causes muscle wasting in uremia, as well as the role UPS plays in the regulation of cellular functions, ranging from the control of the cell cycle to activities that promote cancer. Indeed, inhibitors of proteasome activity have emerged as novel chemothera- peutic agents. Involvement of the UPS in such a wide range of functions explains why the 2004 Nobel Prize in Chemistry was awarded to Avram Hershko, Aaron Ciechanover, and Irwin Rose for their discovery of Ub