Muscle wasting from kidney failure-a model for catabolic conditions

Abstract

Purpose: Muscle atrophy is a frequent complication of chronic kidney disease (CKD) and is associated with increased morbidity and mortality. The processes causing loss of muscle mass are also present in several catabolic conditions. Understanding the pathogenesis of CKD-induced muscle loss could lead to therapeutic interventions that prevent muscle wasting in CKD and potentially, other catabolic conditions.

Major findings: Insulin or IGF-1 resistance caused by CKD, acidosis, inflammation, glucocorticoids or cancer causes defects in insulin-stimulated intracellular signaling that suppresses IRS-1 activity leading to decreased phosphorylation of Akt (p-Akt). A low p-Akt activates caspase-3 which provides muscle proteins substrates of the ubiquitin-proteasome system (UPS). A low p-Akt also leads to decreased phosphorylation of forkhead transcription factors which enter the nucleus to stimulate the expression of atrogin-1/MAFbx and MuRF1, E3 ubiquitin ligases that can be associated with proteolysis of muscle cells by the UPS. Caspase-3 also stimulates proteasome-dependent proteolysis in muscle.

Summary: In CKD, diabetes, inflammatory conditions or in response to acidosis or excess glucocorticoids, insulin resistance develops, initiating reduced IRS-1/PI3K/Akt signaling. In CKD, this reduces p-Akt which stimulates muscle proteolysis by activating caspase-3 and the UPS. Second, caspase-3 cleaves actomyosin yielding substrates for the UPS and increased proteasome-mediated proteolysis. Third, p-Akt down-regulation suppresses myogenesis in CKD. Fourth, exercise in CKD stimulates insulin/IGF-1 signaling to reduce muscle atrophy. Lastly, there is evidence that microRNAs influence insulin signaling providing a potential opportunity to design therapeutic interventions. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting.

Keywords: Acidosis; Cancer; Diabetes; Inflammation and glucocorticoid excess; Kidney failure.

Figure 1. MicroRNAs regulate IGF/PI3K/Akt signaling to change muscle protein metabolism

Muscle-specific microRNAs, miR-1, miR-206 and miR-133 down-regulate IGF/PI3K/Akt signaling by directly targeting IGF-1. Activated IGF-1 reciprocally regulates miR-1 expression via changes in the activation of FoxO transcription factors as FoxO can bind to the miR-1 promoter, increasing miR-1 transcription. IGF-ll is a target of miR-125b while miR-133 can bind to the 3′-UTR of the IGF-1 receptor (IGF-1R), resulting in decreased abundance of the IGF-1 receptor (IGF-1R). miR-486 and miR-17–92 downregulate PTEN, increasing the level of p-Akt which phosphorylates FoxO resulting in its inactivation and this in turn limits muscle protein wasting. miR-23a suppresses translation of both atrogin-1/MAFbx and MuRF1 by interacting with their 3′-UTR’s; this can inhibit muscle atrophy. microRNA Factors that stimulate muscle growth Factors that inhibit muscle growth Decrease or inhibit Increase or stimulate Indirectly decrease or inhibit