<i>miR-26a</i> Limits Muscle Wasting and Cardiac Fibrosis through Exosome-Mediated microRNA Transfer in Chronic Kidney Disease

Abstract

Uremic cardiomyopathy and muscle atrophy are associated with insulin resistance and contribute to chronic kidney disease (CKD)-induced morbidity and mortality. We hypothesized that restoration of <i>miR-26a</i> levels would enhance exosome-mediated microRNA transfer to improve muscle wasting and cardiomyopathy that occur in CKD. <b>Methods:</b> Using next generation sequencing and qPCR, we found that CKD mice had a decreased level of <i>miR-26a</i> in heart and skeletal muscle. We engineered an exosome vector that contained <i>Lamp2b,</i> an exosomal membrane protein gene fused with a muscle-specific surface peptide that targets muscle delivery. We transfected this vector into muscle satellite cells and then transduced these cells with adenovirus that expresses <i>miR-26a</i> to produce exosomes encapsulated <i>miR-26a</i> (Exo/<i>miR-26a</i>). Exo/<i>miR-26a</i> was injected once per week for 8 weeks into the tibialis anterior (TA) muscle of 5/6 nephrectomized CKD mice. <b>Results:</b> Treatment with Exo/<i>miR-26a</i> resulted in increased expression of <i>miR-26a</i> in skeletal muscle and heart. Overexpression of <i>miR-26a</i> increased the skeletal muscle cross-sectional area, decreased the upregulation of FBXO32/atrogin-1 and TRIM63/MuRF1 and depressed cardiac fibrosis lesions. In the hearts of CKD mice, FoxO1 was activated, and connective tissue growth factor, fibronectin and collagen type I alpha 1 were increased. These responses were blunted by injection of Exo/<i>miR-26a</i>. Echocardiograms showed that cardiac function was improved in CKD mice treated with Exo/<i>miR-26a</i>. <b>Conclusion:</b> Overexpression of <i>miR-26a</i> in muscle prevented CKD-induced muscle wasting and attenuated cardiomyopathy via exosome-mediated <i>miR-26a</i> transfer. These results suggest possible therapeutic strategies for using exosome delivery of <i>miR-26a</i> to treat complications of CKD.