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

• Published in: Theranostics Vol. 9; no. 7; pp. 1864 - 1877
• Main Authors: Wang, Bin, Zhang, Aiqing, Wang, Haidong, Klein, Janet D., Tan, Lin, Wang, Ze-Mu, Du, Jie, Naqvi, Nawazish, Liu, Bi-Cheng, Wang, Xiaonan H.
• Format: Journal Article
• Language: English
• Published: Australia Ivyspring International Publisher 01.01.2019
• Subjects: Animals; Collagen Type I - metabolism; Connective Tissue Growth Factor - metabolism; Exosomes - metabolism; Fibronectins - metabolism; Fibrosis - metabolism; Forkhead Box Protein O1 - metabolism; Mice; Mice, Inbred C57BL; MicroRNAs - metabolism; Muscle, Skeletal - metabolism; Muscular Atrophy - metabolism; Myoblasts - metabolism; Myocardium - metabolism; Renal Insufficiency, Chronic - metabolism; Research Paper; Signal Transduction - physiology; Up-Regulation - physiology; surface peptide; Lamp2b; uremic cardiomyopathy; insulin resistance; muscle wasting
• ISSN: 1838-7640; 1838-7640
• DOI: 10.7150/thno.29579

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 levels would enhance exosome-mediated microRNA transfer to improve muscle wasting and cardiomyopathy that occur in CKD. Using next generation sequencing and qPCR, we found that CKD mice had a decreased level of in heart and skeletal muscle. We engineered an exosome vector that contained 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 to produce exosomes encapsulated (Exo/ ). Exo/ was injected once per week for 8 weeks into the tibialis anterior (TA) muscle of 5/6 nephrectomized CKD mice. Treatment with Exo/ resulted in increased expression of in skeletal muscle and heart. Overexpression of 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/ . Echocardiograms showed that cardiac function was improved in CKD mice treated with Exo/ . Overexpression of in muscle prevented CKD-induced muscle wasting and attenuated cardiomyopathy via exosome-mediated transfer. These results suggest possible therapeutic strategies for using exosome delivery of to treat complications of CKD.