Muscle‐derived exosome/miRNA‐26a attenuates skeletal muscle wasting and cardiomyopathy in chronic kidney disease (CKD) mice

Abstract

IntroductionUremic 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.MethodsWe 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 generated in muscle satellite cells and injected into the tibialis anterior (TA) muscle of CKD mice (5/6 subtotal nephrectomy) for 12 weeks. NanoSight instrument was used to quantify exosomes. A miR deep sequencing assay and qPCR were used to identify microRNA expression. Cardiac ultrasound was used to detect heart size and function. In‐Vivo Xtreme camera system was used to detect exosome in vivo.ResultsmiR‐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 upregulation 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.ConclusionsOverexpression of miR‐26a in muscle prevents CKD‐induced muscle loss and attenuates cardiac fibrosis via exosome‐mediated muscle‐heart crosstalk.Support or Funding InformationNational Natural Science Foundation of China (81700618), National Key Research Program (2018YFC130046, 2018YFC1314000). imageThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.