1. Academic Validation
  2. MicroRNA-193b impairs muscle growth in mouse models of type 2 diabetes by targeting the PDK1/Akt signalling pathway

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

  • Diabetologia. 2022 Mar;65(3):563-581. 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 6
Affiliations

Affiliations

  • 1 Department of Endocrinology, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), Shenzhen, China.
  • 2 Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou, China.
  • 3 Department of Endocrinology, Key Laboratory of Endocrinology, National Health Commission, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
  • 4 Department of Geriatrics, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), Shenzhen, China. liang.zhen@szhospital.com.
  • 5 Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China. lu.yan2@zs-hospital.sh.cn.
  • 6 Department of Endocrinology, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), Shenzhen, China. jialijing2012@126.com.
Abstract

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 HbA1c, 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.

Keywords

Akt; Muscles atrophy; PDK1; Type 2 diabetes; miR-193b.

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