Journal
THERANOSTICS
Volume 9, Issue 7, Pages 1864-1877Publisher
IVYSPRING INT PUBL
DOI: 10.7150/thno.29579
Keywords
uremic cardiomyopathy; muscle wasting; insulin resistance; surface peptide; Lamp2b
Categories
Funding
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) of the National Institutes of Health [R01 AR060268]
- American Heart Association Discover and Innovation Grants
- Bayer Group [17IBDG33780000]
- National Natural Science Foundation of China [81700618, 31772690]
- Natural Science Foundation of Jiangsu Province [BK20181487, BK20161071]
- China Young Nephrologist Research Funding
- Fundamental Research Funds for the Central Universities [2242018K41089]
- National Key Research Program [2018YFC1314000]
- Genomics core of Yerkes National Primate Research Center [NIH ORIP/OD P51OD011132]
- Emory Integrated Genomics Core (EIGC) - Emory University School of Medicine
- NIH [UL1TR000454]
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [UL1TR000454] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [R01AR060268] Funding Source: NIH RePORTER
- OFFICE OF THE DIRECTOR, NATIONAL INSTITUTES OF HEALTH [P51OD011132] Funding Source: NIH RePORTER
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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 miR-26a levels would enhance exosome-mediated microRNA transfer to improve muscle wasting and cardiomyopathy that occur in CKD. Methods: Using next generation sequencing and qPCR, we found that CKD mice had a decreased level of miR-26a in heart and skeletal muscle. We engineered an exosome vector that contained Lamp2b, 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 miR-26a to produce exosomes encapsulated miR-26a (Exo/miR-26a). Exo/miR-26a was injected once per week for 8 weeks into the tibialis anterior (TA) muscle of 5/6 nephrectomized CKD mice. Results: Treatment with Exo/miR-26a resulted in increased expression of miR-26a in skeletal muscle and heart. Overexpression of miR-26a 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/miR-26a. Echocardiograms showed that cardiac function was improved in CKD mice treated with Exo/miR-26a. Conclusion: Overexpression of miR-26a in muscle prevented CKD-induced muscle wasting and attenuated cardiomyopathy via exosome-mediated miR-26a transfer. These results suggest possible therapeutic strategies for using exosome delivery of miR-26a to treat complications of CKD.
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