Pathogenesis of uremic sarcopenia based on metabolic alteration

Abstract

Sarcopenia, the degenerative loss of skeletal muscle mass, is associated with increased morbidity and mortality for patients with chronic kidney disease (CKD), where it is specifically referred to as uremic sarcopenia. However, the details of the abnormal metabolic processes induced by uremic toxins remain unclear. Recently, we clarified the pathogenic mechanisms of uremic sarcopenia using liquid chromatography-mass spectrometry (MS) and MS imaging, which revealed that uremic toxin indoxyl sulfate accumulates in the muscle tissue of CKD model mice. Moreover, capillary electrophoresis MS-metabolomics of a muscle cell line suggested that indoxyl sulfate induces metabolic alterations such as upregulation of glycolysis, including the pentose phosphate pathway, for protection against oxidative stress. This altered metabolic flow leads to downregulation of the tricarboxylic acid cycle resulting in an ATP shortage. In a clinical study, plasma indoxyl sulfate levels were associated with skeletal muscle mass reduction in CKD patients. In this review, I discuss the known pathogenic mechanisms of uremic sarcopenia induced by the uremic toxin indoxyl sulfate with a focus on the consequent metabolic alteration and mitochondrial dysfunction.