MicroRNA-193b impairs muscle growth in mouse models of type 2 diabetes by targeting the PDK1/Akt signalling pathway,Diabetologia

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MicroRNA-193b impairs muscle growth in mouse models of type 2 diabetes by targeting the PDK1/Akt signalling pathway
Diabetologia ( IF 8.4 ) Pub Date : 2021-12-16 , DOI: 10.1007/s00125-021-05616-y
Shu Yang _{1,

2} , Guangyan Yang ₁ , Han Wu _{1,

3} , Lin Kang ₁ , Jiaqing Xiang ₁ , Peilin Zheng ₁ , Shanhu Qiu ₁ , Zhen Liang ₄ , Yan Lu ₅ , Lijing Jia ₁

Affiliation

Aims/hypothesis

Type 2 diabetes is associated with a reduction in skeletal muscle mass; however, how the progression of sarcopenia is induced and regulated remains largely unknown. We aimed to find out whether a specific microRNA (miR) may contribute to skeletal muscle atrophy in type 2 diabetes.

Methods

Adeno-associated virus (AAV)-mediated skeletal muscle miR-193b overexpression in C57BLKS/J mice, and skeletal muscle miR-193b deficiency in db/db mice were used to explore the function of miR-193b in muscle loss. In C57BL/6 J mice, tibialis anterior-specific deletion of 3-phosphoinositide-dependent protein kinase-1 (PDK1), mediated by in situ AAV injection, was used to confirm whether miR-193b regulates muscle growth through PDK1. Serum miR-193b levels were also analysed in healthy individuals (n = 20) and those with type 2 diabetes (n = 20), and correlations of miR-193b levels with HbA_1c, fasting blood glucose (FBG), body composition, triacylglycerols and C-peptide were assessed.

Results

In this study, we found that serum miR-193b levels increased in individuals with type 2 diabetes and negatively correlated with muscle mass in these participants. Functional studies further showed that AAV-mediated overexpression of miR-193b induced muscle loss and dysfunction in healthy mice. In contrast, suppression of miR-193b attenuated muscle loss and dysfunction in db/db mice. Mechanistic analysis revealed that miR-193b could target Pdk1 expression to inactivate the Akt/mammalian target of rapamycin (mTOR)/p70S6 kinase (S6K) pathway, thereby inhibiting protein synthesis. Therefore, knockdown of PDK1 in healthy mice blocked miR-193b-induced inactivation of the Akt/mTOR/S6K pathway and impairment of muscle growth.

Conclusions/interpretation

Our results identified a previously unrecognised role of miR-193b in muscle function and mass that could be a potential therapeutic target for treating sarcopenia.

Graphical abstract

中文翻译：

MicroRNA-193b 通过靶向 PDK1/Akt 信号通路损害 2 型糖尿病小鼠模型的肌肉生长

目标/假设

2 型糖尿病与骨骼肌量减少有关；然而，如何诱导和调节肌肉减少症的进展仍然很大程度上未知。我们旨在找出特定的 microRNA (miR) 是否可能导致 2 型糖尿病的骨骼肌萎缩。

方法

使用腺相关病毒 (AAV) 介导的 C57BLKS/J 小鼠骨骼肌 miR-193b 过表达和db/db小鼠骨骼肌 miR-193b 缺陷来探索 miR-193b 在肌肉损失中的功能。在 C57BL/6 J 小鼠中，通过原位 AAV 注射介导的 3-磷酸肌醇依赖性蛋白激酶-1 (PDK1) 的胫骨前肌特异性缺失被用于确认 miR-193b 是否通过 PDK1 调节肌肉生长。还分析了健康个体 ( n = 20) 和 2 型糖尿病患者 ( n = 20) 的血清 miR-193b 水平，以及 miR-193b 水平与 HbA _1c、空腹血糖 (FBG)、身体成分、三酰基甘油的相关性和 C 肽进行了评估。

结果

在这项研究中，我们发现 2 型糖尿病患者的血清 miR-193b 水平升高，并且与这些参与者的肌肉质量呈负相关。功能研究进一步表明，AAV 介导的 miR-193b 过表达会导致健康小鼠的肌肉损失和功能障碍。相反，抑制 miR-193b 可减轻db/db小鼠的肌肉损失和功能障碍。机理分析表明，miR-193b 可以靶向Pdk1表达，使 Akt/哺乳动物雷帕霉素靶蛋白 (mTOR)/p70S6 激酶 (S6K) 通路失活，从而抑制蛋白质合成。因此，在健康小鼠中敲低 PDK1 可阻止 miR-193b 诱导的 Akt/mTOR/S6K 通路失活和肌肉生长受损。