530 myofibrils (i.e. actin, myosin, troponin, or tropomyosin), but it does not readily break up the myofibril into its main component proteins [39]. This means that another proteo- lytic system must initially digest myofibrils to create substrates that can be degraded by the UPS [40]. Many catabolic conditions are associated with inflam- mation and/or cell injury, and these conditions activate a cysteine protease called caspase-3. We tested caspase-3 in an in vitro system using purified actomyosin and found that caspase-3 cleaves actomyosin and leaves a characteristic 14kD actin fragment [40]. When we activated caspase-3 in cultured muscle cells, we found that UPS rapidly degraded myofibrillar component proteins, and again, the 14kD C-terminal fragment of actin was left in the muscle cells [40]. The protein-cleaving action of caspase-3 is important because blocking caspase-3 will reduce overall protein degradation in muscle [40]. In addition, we have found the same cleavage processes are present in muscles of rodent models of uremia, type-1 or type-2 diabetes, or in Ang-II- induced hypertension [7, 35, 40, 41]. Moreover, we found that the 14kD actin fragment also accumulates in muscles of patients with loss of muscle mass due to painful osteodystrophy, uremia, or burn injury [42]. In the latter study, we found that the rate of protein degradation in muscle (measured from the turnover of labeled amino acids) directly correlated (r = 0.78) with the level of the 14kD actin fragment in the same muscle. In addition, there Pediatr Nephrol (2008) 23:527–535 was a lower level of the 14kD actin fragment in muscle of hemodialysis patients who participated in 18 weeks of an endurance exercise training program. In summary, the level of the 14kD actin fragment is directly associated with measured protein degradation in muscle, and the accumu- lation of the fragment responds to a beneficial therapeutic intervention. If these properties hold up in other trials, the level of the 14kD actin fragment could be used as a “biomarker” of increased muscle protein degradation [42]. Signals triggering muscle atrophy in kidney disease and other catabolic states Complications of CKD, as well as the complex syndrome of uremia, can trigger muscle protein breakdown. The triggering complications include metabolic acidosis, de- creased insulin action (including insulin resistance), in- creased glucocorticoid production, high levels of Ang II, and inflammation [5–8]. Metabolic acidosis is known to cause accelerated protein degradation in infants, children, adults, the elderly, and patients with CKD (Table 1). The mechanism by which metabolic acidosis causes muscle wasting involves activation of the UPS and caspase-3 [40, 43]. In addition, acidosis changes hormone actions, such as insulin resistance and increased glucocorticoid production, which are involved in activating protein degradation [32, 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 Infants [68] Children with CKD [69] Normal adults [70] Normal adults [71] Chronic renal failure [72] Chronic renal failure [73] Chronic renal failure [74] Chronic renal failure [75] Hemodialysis [76] Hemodialysis [77] CAPD [78] CAPD [79] Outcome measurements Trial outcome Low-birth-weight, acidotic infants were given NaHCO3 or NaCl Measured rates of protein degradation in children with CKD Acidosis induced and then measured amino acid and protein metabolism Induced acidosis and then measured nitrogen balance and albumin synthesis Nitrogen balance before and after treatment of acidosis Essential amino acid and protein degradation before and after treatment of acidosis Muscle protein degradation and degree of acidosis Nitrogen balance before and after treatment of acidosis Protein degradation before and after treatment of acidosis Serum albumin before and after treatment of acidosis Protein degradation before and after treatment of acidosis Weight and muscle gain before and after treatment of acidosis NaHCO3 supplement improved growth Protein loss was ∼ 2-fold higher when HCO3 was < 16 mM compared with > 22.6 mM Acidosis increased amino acid and protein degradation Acidosis induced negative nitrogen balance and suppressed albumin synthesis NaHCO3 improved nitrogen balance NaHCO3 suppressed amino acid and protein degradation Proteolysis was proportional to acidosis and blood cortisol NaHCO3 reduced urea production and improved nitrogen balance NaHCO3 decreased protein degradation NaHCO3 increased serum albumin NaHCO3 decreased protein degradation Raising dialysis buffer increased weight and muscle mass CAPD continuous ambulatory peritoneal dialysis