Decreased miRNA-148a-3p expression in skeletal muscle of patients with chronic kidney disease

Introduction: Skeletal muscle wasting is a common complication of chronic kidney disease which leads to a loss of muscle function. The pathogenesis of skeletal muscle wasting is incompletely understood, which is preventing the development of targeted therapeutics. Recent evidence implicates miRNAs in the of skeletal muscle wasting. Our aim was to firstly examine miRNA profiles of CKD human skeletal muscle for the identification of aberrant expression patterns compared to a healthy control (HC) cohort, and secondly, investigate the role these miRNAs may play in inducing or promoting skeletal muscle atrophy using a novel human primary skeletal muscle cell model of CKD skeletal muscle. Methods: For comparison between CKD and HC populations, skeletal muscle biopsies were collected from the vastus lateralis of n=15 CKD patients stage 3b-5, and n=15 HC individuals matched for age, gender and physical activity. n=5 biopsies from each group underwent next generation sequencing to obtain complete mnicroRNA profiles in CKD versus HC cohorts, which were then validated in a seperate cohort (n=10 in each group) by PCR. A causative role in muscle wasting was determined by transfection of key microRNAs by 3H-phenylalanine release into the media. Results: Next Generation Sequencing identified differential expression of 16 miRNAs in skeletal muscle of CKD patients versus controls, and PCR validation confirmed miRNA-148a-3p expression was significantly decreased in CKD patients. The reduced miRNA-148a-3p expression was also maintained in the primary culture model. Upon overexpression of miRNA-148a-3p in CKD myotubes, protein degradation rates were decreased non-significantly (p=0.28) by 16.3% compared to un-transfected CKD cells. Conclusion: CKD was associated with a significant reduction in miRNA-148a-3p expression in skeletal muscle compared to non-CKD controls which was retained in our in vitro model. Overexpression of miRNA-148a-3p in primary skeletal myotubes non-significantly decreased muscle protein degradation by 16.3%. In order to determine the importance of miRNA-148a-regulation of protein degradation, a deeper understanding of miRNA-148a-3p targets and their associated pathways with respect to those dysregulated in skeletal muscle wasting is required. ### Competing Interest Statement The authors have declared no competing interest.