miRNA-23a/27a attenuates muscle atrophy and renal fibrosis through muscle-kidney crosstalk

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)

Aiqing,Li,Min,Wang,Bin,Klein,Janet D.,Price,S. Russ,Wang,Xiaonan H. Zhang (Creator)

Institution

East Carolina University (ECU )

Web Site: http://www.ecu.edu/lib/

Abstract: Background The treatment of muscle wasting is accompanied by benefits in other organs, possibly resulting from muscle-- organ crosstalk. However, how the muscle communicates with these organs is less understood. Two microRNAs (miRs), miR-23a and miR-27a, are located together in a gene cluster and regulate proteins that are involved in the atrophy process. MiR-23a/27a has been shown to reduce muscle wasting and act as an anti-fibrotic agent. We hypothesized that intramus- cular injection of miR-23a/27a would counteract both muscle wasting and renal fibrosis lesions in a streptozotocin-induced diabetic model.Methods We generated an adeno-associated virus (AAV) that overexpresses the miR-23a∼27a∼24-2 precursor RNA and injected it into the tibialis anterior muscle of streptozotocin-induced diabetic mice. Muscle cross-section area (immunohistology plus software measurement) and muscle function (grip strength) were used to evaluate muscle atrophy. Fibrosis-related proteins were measured by western blot to monitor renal damage. In some cases, AAV-GFP was used to mimic the miR movement in vivo, allowing us to track organ redistribution by using the Xtreme Imaging System.Results The injection of AAV-miR-23a/27a increased the levels of miR-23a and miR-27a as well as increased phosphorylated Akt, attenuated the levels of FoxO1 and PTEN proteins, and reduced the abundance of TRIM63/MuRF1 and FBXO32/atrogin-1 in skeletal muscles. It also decreased myostatin mRNA and protein levels as well as the levels of phosphorylated pSMAD2/3. Provision of miR-23a/27a attenuates the diabetes-induced reduction of muscle cross-sectional area and muscle function. Cu- riously, the serum BUN of diabetic animals was reduced in mice undergoing the miR-23a/27a intervention. Renal fibrosis, eval- uated by Masson trichromatic staining, was also decreased as were kidney levels of phosphorylated SMAD2/3, alpha smooth muscle actin, fibronectin, and collagen. In diabetic mice injected intramuscularly with AAV-GFP, GFP fluorescence levels in the kidneys showed linear correlation with the levels in injected muscle when examined by linear regression. Following intramus- cular injection of AAV-miR-23a∼27a∼24-2, the levels of miR-23a and miR-27a in serum exosomes and kidney were significantly increased compared with samples from control virus-injected mice; however, no viral DNA was detected in the kidney. Conclusions We conclude that overexpression of miR-23a/27a in muscle prevents diabetes-induced muscle cachexia and at- tenuates renal fibrosis lesions via muscle--kidney crosstalk. Further, this crosstalk involves movement of miR potentially through muscle originated exosomes and serum distribution without movement of AAV. These results could provide new ap- proaches for developing therapeutic strategies for diabetic nephropathy with muscle wasting.

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Other

Language: English

Date: 2018

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