MicroRNA Expression and Muscle Wasting in Chronic Kidney Disease

Skeletal muscle wasting is a common complication of chronic kidney disease (CKD), resulting in a loss of muscle mass, strength and function, reduced quality of life, and increased morbidity and mortality. Research has identified aberrant microRNA (miRNA) expression and regulation in the development of muscle atrophy in both primary and secondary muscle wasting conditions. Data from a limited number of studies that specifically investigate the role of miRNAs in animal models of CKD muscle wasting suggest that miRNAs are pivotal to the dysregulated protein metabolism seen in this population. In addition, there is also emerging evidence for the involvement of miRNAs in a beneficial crosstalk system between skeletal muscle and other organs that may potentially limit CKD progression. However, current knowledge about the role of miRNAs in both muscle wasting and crosstalk is restricted to animal models of CKD, demonstrating a clear need to identify miRNAs central to these processes in human CKD.

Next Generation Sequencing identified differential expression of 16 miRNAs in skeletal muscle of CKD patients versus controls. Validation confirmed miRNA-148a-3p expression was significantly decreased in CKD patients, and the role of miRNA-148a-3p was subsequently explored in a novel human primary cell model of CKD skeletal muscle. This model retained the CKD phenotype in vitro and displayed reduced miRNA-148a-3p expression, though, miRNA-148a-3p overexpression did not significantly decrease protein degradation rates or E3 ubiquitin ligase expression. However, target analysis identified several miRNA-148a-3p targets, indicating a role for miRNA-148a-3p in the regulation of apoptosis and autophagy in skeletal muscle. Furthermore, plasma exosome miRNA expression was assessed in CKD patients versus controls and identified increased miRNA-21-5p, miRNA-22-3p, miRNA-191-5p, miRNA-29c-3p, miRNA-126-3p, 148a-3p and miRNA-26a-5p in CKD patients. These miRNAs positively associated with adverse cardiovascular phenotypes in haemodialysis patients, highlighting the potential role of miRNAs in the development and progression of uraemic cardiomyopathy.