Maintenance of protein stores in chronic kidney disease 1 2 3 4 5 8 5 9 10 5 11 The ATP-dependent, ubiquitin–proteasome system (UPS) 1 12 13 14 Fig. 1 15  10 15 Since the initial reports that the UPS recognizes specific proteins and tags them for destruction, knowledge about proteolytic processes in the proteasome has exploded. Thousands of proteins have been recognized as being degraded by the UPS, and novel cellular functions are now known to be regulated by Ub conjugation. In terms of protein breakdown, the major functions of the pathway are: Rapid removal of proteins Regulation of gene transcription 16 17 18 19 20 21 22 Quality-control mechanism 23 24 Influencing the function of the immune system 15 25 As a source of amino acids Functions of Ub not associated with proteolysis 26 27 Uremia-activated mechanisms that accelerate loss of muscle protein 10 28 5 28 11 29 31 5 6 32 5 6 33 10 3 10 28 34 35 34 36 38 In uremia, the initial cleavage of myofibrillar proteins is mediated by caspase-3 39 40 40 40 40 7 35 40 41 42 r 42 Signals triggering muscle atrophy in kidney disease and other catabolic states 5 8 1 40 43 32 41 43 45 2 1 Table 1 Evidence that metabolic acidosis induces catabolism of protein and amino acids in normal infants, children, and adults, as well as in patients with chronic kidney disease (CKD) Subjects investigated Outcome measurements Trial outcome 68 3 3 69 Measured rates of protein degradation in children with CKD 3 70 Acidosis induced and then measured amino acid and protein metabolism Acidosis increased amino acid and protein degradation 71 Induced acidosis and then measured nitrogen balance and albumin synthesis Acidosis induced negative nitrogen balance and suppressed albumin synthesis 72 Nitrogen balance before and after treatment of acidosis 3 73 Essential amino acid and protein degradation before and after treatment of acidosis 3 74 Muscle protein degradation and degree of acidosis Proteolysis was proportional to acidosis and blood cortisol 75 Nitrogen balance before and after treatment of acidosis 3 76 Protein degradation before and after treatment of acidosis 3 77 Serum albumin before and after treatment of acidosis 3 78 Protein degradation before and after treatment of acidosis 3 79 Weight and muscle gain before and after treatment of acidosis Raising dialysis buffer increased weight and muscle mass CAPD Table 2 Metabolic acidosis in otherwise normal humans changed hormonal levels or responses to hormones Hormone Acidosis-induced response 80 84 Suppressed GH secretion Lower IGF-1 response 44 85 86 Suppressed insulin-stimulated glucose metabolism 81 84 87 Decreased IGF-1 in plasma, and kidney and liver (but not in muscle) 82 88 3 4 89 Increased glucocorticoid production 90 91 Decreased sensitivity of PTH secretion to changes in plasma calcium 91 2 28 2 41 44 46 47 35 48 49 41 35 37 2 Fig. 2 15  35 41 C C 35 35 37 37 32 41 50 32 51 53 7 54 55 56 58 59 7 2 60 61 62 63 64 65 66 67 Conclusion http://nobelprize.org/chemistry/laureates/2004/