miRNA-23a/27a attenuates muscle atrophy and renal fibrosis through muscle-kidney crosstalk.
miRNA-23a/27a attenuates muscle atrophy and renal fibrosis through muscle-kidney crosstalk.
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DOI：
10.1002/jcsm.12296
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发表时间：
2018-08
期刊：
影响因子：
--
通讯作者：
Wang XH
中科院分区：
文献类型：
--
作者：
Zhang A;Li M;Wang B;Klein JD;Price SR;Wang XH
肌肉萎缩的治疗还伴随着其他器官的益处，可能是肌肉-器官串扰的结果。然而，肌肉是如何与这些器官交流的，人们却知之甚少。两个microRNAs(MiR)，miR-23a和miR-27a，一起位于一个基因簇中，调节参与萎缩过程的蛋白质。MIR-23a/27a已被证明可以减少肌肉损耗，并作为一种抗纤维化药物。我们假设肌肉注射miR-23a/27a可以对抗链脲佐菌素诱导的糖尿病模型中的肌肉萎缩和肾脏纤维化损害。我们构建了一种高表达miR-23a∼27A∼24-2前体基因的腺相关病毒，并将其注射到链脲佐菌素诱导的糖尿病小鼠的胫前肌中。肌肉横截面积(免疫组织学加软件测量)和肌肉功能(握力)用于评估肌肉萎缩。免疫印迹法检测肾组织纤维化相关蛋白，监测肾损害情况。在某些情况下，AAV-GFP被用来模拟miR在体内的运动，使我们能够通过使用Xtreme成像系统来跟踪器官的重新分布。注射AAV-miR-23a/27a可增加骨骼肌中miR-23a和miR-27a的表达，增加Akt的磷酸化水平，降低FoxO1和PTEN蛋白的表达水平，降低TRIM63/MuRF1和FBXO32/阿托金-1的丰度。MiR-23a/27A的提供减轻了糖尿病引起的肌肉横截面积和肌肉功能的减少。奇怪的是，在接受miR-23a/27A干预的小鼠中，糖尿病动物的血清BUN降低了。通过Masson三色染色评估的肾纤维化也降低了肾脏磷酸化Smad2/3、α-平滑肌肌动蛋白、纤维连接蛋白和胶原的水平。在肌肉注射AAV-GFP的糖尿病小鼠中，经线性回归检验，肾脏中的GFP荧光水平与肌肉中的水平呈线性相关。肌肉注射AAv-miR-23a∼27A∼24-2后，小鼠血清和肾脏中miR-23a和miR-27a的表达水平均显著高于对照组，而肾脏中未检测到病毒。我们的结论是，miR-23a/27a在肌肉中的过表达通过肌肉-肾脏串扰防止了糖尿病引起的肌肉恶病质，并减轻了肾脏纤维化损害。此外，这种串扰涉及miR可能通过肌源性外切体的移动和血清分布，而不涉及AAV的移动。这些结果可能为开发糖尿病肾病伴肌肉萎缩的治疗策略提供新的方法。
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 intramuscular injection of miR‐23a/27a would counteract both muscle wasting and renal fibrosis lesions in a streptozotocin‐induced diabetic model. 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. 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. Curiously, the serum BUN of diabetic animals was reduced in mice undergoing the miR‐23a/27a intervention. Renal fibrosis, evaluated 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 intramuscular 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. We conclude that overexpression of miR‐23a/27a in muscle prevents diabetes‐induced muscle cachexia and attenuates 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 approaches for developing therapeutic strategies for diabetic nephropathy with muscle wasting.
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DOI：
10.1038/nri3622
发表时间：
2014-03
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
24.5
作者：
Pan, Qiuwei;Ramakrishnaiah, Vedashree;van der Laan, Luc J. W.
通讯作者：
van der Laan, Luc J. W.
DOI：
10.1097/spc.0b013e32834bddf9
发表时间：
2011-12-01
影响因子：
2.1
作者：
Han, H Q;Mitch, William E
通讯作者：
Mitch, William E
DOI：
10.1159/000324934
发表时间：
2011-01-01
期刊：
DIABETES AND THE KIDNEY
影响因子：
--
作者：
Reutens, Anne T.;Atkins, Robert C.
通讯作者：
Atkins, Robert C.
影响因子：
6.7
作者：
Boon, Reinier A.;Hergenreider, Eduard;Dimmeler, Stefanie
通讯作者：
Dimmeler, Stefanie