Abstract: SA-PO140

Exogenous miRNA-23a/27a Attenuates Diabetes-Related Muscle Atrophy and Renal Fibrotic Lesions

Session Information

Category: Diabetes

  • 503 Diabetes Mellitus and Obesity: Translational

Authors

  • Wang, Bin, Emory University, Atlanta, United States
  • Zhang, Aiqing, Emory University, Atlanta, United States
  • Hasounah, Faten, Emory University, Atlanta, Georgia, United States
  • Wang, Xiaonan H., Emory University, Atlanta, Georgia, United States
Background

Muscle atrophy is a frequent complication of diabetes mellitus. The microRNA-23a, -27a and 24-2, are located together in a gene cluster on chromosome 8. MiR-23a and miR-27a are known to regulate proteins that are involved in the atrophy and fibrosis process. We hypothesized that treatment with miR-23a/27a would reduce both diabetes-induced muscle wasting and renal fibrosis through exosome-mediated muscle-kidney crosstalk.

Methods

We generated an adeno-associated virus (AAV) that overexpresses miR-23a~27a~24-2 precursor RNA (and an AAV-GFP control) and injected it into the tibialis anterior (TA) muscle of STZ-induced diabetic mice. After 3 months, mice were killed and muscles and kidneys were analyzed for protein markers of atrophy and fibrosis. In-Vivo Xtreme camera system was used to track GFP migration to kidney in vivo.

Results

Injection of AAV-miRs into muscle increased miR-23a and miR-27a. The insulin/IGF signaling pathway was upregulated in skeletal muscle; e.g., increased phosphorylated Akt, attenuated FoxO1 and PTEN, reduced TRIM63/MuRF1 and FBXO32/atrogin-1. Myostatin signaling was downregulated; e.g., decreased myostatin and phosphorylated SMAD2/3 protein levels. Curiously, the serum BUN of diabetic animals was reduced in mice undergoing the miR-23a/27a intervention in muscle. Renal fibrosis, evaluated by Masson trichrome, was decreased as were pSMAD2/3, alpha smooth muscle actin, fibronectin and collagens. When diabetic mice were injected intramuscularly with AAV-GFP, the kidneys showed GFP fluorescence at levels that correlated with the levels in injected muscle, examined by linear regression. The abundance of GFP protein in skeletal muscle, serum exosomes and kidney increased over time after injection. Serum exosomes and kidneys of mice that received intramuscular injections of miR-23a/27a showed levels of those miRs that were higher than the un-injected control mice. No viral DNA was detected in the kidney.

Conclusion

Overexpression of miR-23a/27a in muscle prevents diabetes-induced muscle loss and attenuates renal fibrosis lesions via exosome-mediated muscle-kidney crosstalk.

Funding

  • Other NIH Support