Going micro in CKD-related cachexia

Abstract

Muscle wasting in chronic kidney diseases (CKDs), sometimes referred to as protein energy wasting or cachexia, has been widely studied, yet much remains to be understood about the underlying pathophysiology. CKD-related changes in cell signaling disrupt proteostasis by activating muscle proteolysis [e.g. ubiquitin–proteasome system (UPS), autophagy and caspase-3] and negatively impacting protein synthesis and muscle regeneration. Muscle mass is controlled by a variety of signaling pathways, the most prominent being the insulin-GF-1)/Phosphatidylinositide 3-kinase (PI3K)/Protein Kinase B (Akt) pathway, which provides a point of intersection for protein synthesis, protein degradation and myogenesis. Akt phosphorylates and activates mTOR, which in turn stimulates key components of the protein synthesis and myoblast differentiation machineries. In contrast, Akt phosphorylates and inhibits the Forkhead box class O (FOXO) transcription factors, which increase the expression of several atrophy-inducing proteins including atrogin-1/MAFbx and Muscle RING finger 1 (MURF1) [ 1]. Other important signaling pathways include the Janus kinase/signal transducers and activators of transcription (JAK/STAT) and Activin receptor-IIB (ActRIIB)/SMAD pathways, which mediate the effects of cytokines [e.g. interleukin-6 (IL-6)] and the muscle-specific autocrine factor, myostatin (also called GDF-8), respectively [ 2].