title: Cellular mechanisms causing loss of muscle mass in kidney disease.
abstract: In stable adults or patients with kidney disease, the daily turnover of cellular proteins is very large, amounting to the quantity of protein in 1 to 1.5 kg of muscle. Consequently, even a small but persistent increase in protein degradation or decrease in protein synthesis leads to a substantial loss of muscle mass. In chronic kidney disease, the pathway that degrades muscle protein is the ubiquitin-proteasome system. We tested whether either of two complications of chronic kidney disease, metabolic acidosis or insulin resistance accelerates the loss of muscle protein. Metabolic acidosis activates the ubiquitin-proteasome system and this can explain an large number of clinical conditions in which metabolic acidosis also causes loss of muscle protein. Insulin deficiency as a model of insulin resistance also activates the ubiquitin-proteasome system. Both complications also activate caspase-3 and we found that this protease performs a critical initial step in breaking down the complex structure of muscle to provide actin, myosin and fragments of these proteins as substrates for the ubiquitin-proteasome system. Defects in insulin signalling processes can activate both caspase-3 and the ubiquitin-proteasome system to degrade muscle protein. Understanding mechanisms that activate protein breakdown will lead to therapies that successfully prevent the loss of muscle mass in patients with kidney disease.
authors.affiliation: Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: William E
authors.initials: WE
authors.lastname: Mitch
authors.forename: J
authors.initials: J
authors.lastname: Du
mesh_terms: D006801:Humans; D007674:Kidney Diseases / Q000150:complications* / Q000378:metabolism; D009135:Muscular Diseases / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex