Depiction of some of the different pathways that may potentially interact in muscle tissue in CKD affecting protein turnover. Using the example of muscle tissue it can be observed that CKD causes perturbations in a range of factors which are involved in muscle metabolism and protein turnover. Firstly, CKD and uremia causes a decrease in food intake, anorexia by multiple mechanisms including the possible reduction in active ghrelin. Further, therapeutic low protein diets reduce dietary protein intake further and potentially the amino acid pool within muscle. The reduction in dietary intake and amino acids is likely to have a detrimental effect on both direct protein synthetic pathways within muscle (and suppression of protein breakdown, e.g. branched-chain amino acids, BCAAs) but indirectly through insulin and the GH-IGF-1 axis. The GH-IGF-1 axis is further down-regulated in CKD possibly through direct feedback control at the hypothalamus-pituitary level (i.e. via increased corticosteroids and cytokines, and reduced ghrelin) and at a cellular level of GH resistance (potentially via effects of cytokines). GH-IGF-1 has potent effects on amino acid transport, protein synthesis and suppression of protein breakdown (via IGF-1). Insulin resistance is common in CKD and as with other chronic diseases which are characterised by a proinflammatory response. This usually has a general metabolic effect and a local effect in muscle with a reduction in nutrient transport (glucose and amino acids)/responsiveness of the cell and reduction in net protein synthetic rates (effects on breakdown and synthesis). ANG II, cortisol and aldosterone may all reduce insulin sensitivity. Other mediators which may be implicated in human CKD and muscle function include ANG II, aldosterone and vitamin D (and the vitamin D receptor), although their precise roles in muscle protein turnover have yet to be determined. Glucocorticoids which may be increased in levels/activities within CKD may have a typical effect on muscle with an effect on strengthening insulin resistance in particular and increasing protein breakdown. The proinflammatory cytokines which antagonise normal anabolic pathways may also have a direct impact upon protein turnover in muscle in human CKD although this is difficult to evaluate. The net effect may translate to net protein losses, a reduction in nutritional status and muscle wasting. N.b. this loss of protein may come from both skeletal muscle and visceral protein tissues. The significant reduction in nutritional status is associated with increased morbidity and mortality in CKD studies. N.B. Insulin also plays a role in protein synthesis activation within muscle (not shown in diagram, e.g. cross-signalling pathways with IGF-1); the adipocytokine alterations in CKD may affect insulin sensitivity and pathways involved; and androgens are implicated in muscle protein turnover and may also be reduced in CKD ( e.g. hypogonadism in males), although not discussed in detail within this article. Further, an upregulation of myostatin, and downregulation of myogenesis, and satellite cell activities is likely.