Pediatr Nephrol (2008) 23:527–535 DOI 10.1007/s00467-007-0594-z REVIEW Muscle wasting in chronic kidney disease: the role of the ubiquitin proteasome system and its clinical impact Vik R. Rajan & William E. Mitch Received: 7 May 2007 / Revised: 13 June 2007 / Accepted: 14 June 2007 / Published online: 7 November 2007 # IPNA 2007 Abstract Muscle wasting in chronic kidney disease (CKD) and other catabolic diseases (e.g. sepsis, diabetes, cancer) can occur despite adequate nutritional intake. It is now known that complications of these various disorders, including acidosis, insulin resistance, inflammation, and increased glucocorticoid and angiotensin II production, all activate the ubiquitin–proteasome system (UPS) to degrade muscle proteins. The initial step in this process is activation of caspase-3 to cleave the myofibril into its components (actin, myosin, troponin, and tropomyosin). Caspase-3 is required because the UPS minimally degrades the myofibril but rapidly degrades its component proteins. Caspase-3 activity is easily detected because it leaves a characteristic 14kD actin fragment in muscle samples. Preliminary evidence from several experimental models of catabolic diseases, as well as from studies in patients, indicates that this fragment could be a useful biomarker because it correlates well with the degree of muscle degradation in dialysis patients and in other catabolic conditions. Keywords Ubiquitin-proteasome system (UPS) . Caspase-3 . 14kD actin fragment . Muscle wasting . Protein degradation . Muscle atrophy . Uremia . Chronic kidney disease (CKD) V. R. Rajan : W. E. Mitch (*) Nephrology Division M/S: BCM 285, Baylor College of Medicine, One Baylor, Plaza, Alkek N-520, Houston, TX 77030, USA e-mail: mitch@bcm.edu Maintenance of protein stores in chronic kidney disease In uremic patients, protein stores are frequently depressed when assessed by a low serum prealbumin and weight loss, which includes loss of muscle mass [1, 2]. In pediatric patients with chronic kidney disease (CKD), linear growth is impaired and muscle mass is reduced. Although these findings have been attributed to “malnutrition”, many uremic patients with muscle wasting have not developed the problems because of inadequate diet; instead, they have complications that induce a complex series of physiological and biochemical adaptations, resulting in protein catabolism [3, 4]. In children and adults with CKD, these complications include metabolic acidosis, insulin resistance, increased glucocorticoid production, high levels of angiotensin II (Ang II), and inflammation [5–8]. Many observational studies and mechanistic investigations have attempted to explain this loss of protein stores, and especially the loss of muscle mass. There are at least three conclusions from these studies. First, rates of protein synthesis in muscle are generally unchanged, whereas rates of protein degradation tend to increase [5, 9]. Second, the daily rates of protein turnover in cells are so high (3.5–4.5 g protein/kg per day) that even a small increase in protein degradation (and/or a decrease in protein synthesis) will cause marked protein depletion over time [10]. Third, the increase in muscle protein degradation in uremia and most other catabolic disease states is mostly due to programmed activation of the ubiquitin–proteasome system (UPS) [5, 11]. Therefore, to understand muscle wasting, one must understand the UPS.