Xiaonan Wang
Emory University, USA
Title: Muscle-derived miR-26a mediate cardiac fibrosis through exosome in chronic kidney disease mice
Biography
Biography: Xiaonan Wang
Abstract
Uremic cardiomyopathy and muscle atrophy contribute to CKD-induced morbidity and mortality. Exosomes, natural carriers of many signal molecules including microRNA (miR), mediate organ-to-organ communication. We hypothesized that miR-26 would benefit both CKD-induced muscle wasting and cardiomyopathy through exosome-mediated muscle-heart crosstalk. We used an engineered exosome vector, which contains an exosomal membrane protein gene Lamp2b fused with muscle specific surface peptide for targeting delivery. Exosome encapsulated miR-26a precursor RNA (Exo/miR26) were injected into the tibialis anterior (TA) muscle of CKD mice (5/6 subtotal nephrectomy) for 10 weeks. miR-26a was decreased in skeletal muscle and heart of CKD mice. Uremic serum enhanced secretion of miR-26a exosomes in cultured C2C12 skeletal and H9C2 cardiac muscle cells. The intervention of Exo/miR26a increased the expression of miR-26a in skeletal muscle and heart, as well as increased muscle cross-section area and decreased CKD-induced up-regulation of atrogin-1 and MuRF1. Curiously, cardiac fibrosis lesion was partially depressed, and FoxO1, α-SMA, connect tissue growth factor (CTGF), fibronectin and collagen1α were decreased in CKD mice with intramuscular injection of Exo/miR-26a. Echocardiography showed that the percentage of ejection fraction was increased in CKD mice treated with Exo/miR26a. Using fluorescence dye labeled Exo/miR26a; we found that the fluorescence intensity in heart was correlated with skeletal muscle, examined by linear regression. We found that miR-26a directly inhibits FoxO1 and CTGF, which provided mechanism for inhibition of muscle atrophy and cardiac fibrosis by Exo/miR26a. Overexpression of miR-26a in muscle prevents CKD-induced muscle loss and attenuates cardiac fibrosis via exosome-mediated muscle-heart crosstalk.