Research Papers: Pathology:

Dehydroepiandrosterone-induced activation of mTORC1 and inhibition of autophagy contribute to skeletal muscle insulin resistance in a mouse model of polycystic ovary syndrome

Xi Song _, Qiyang Shen, Liting Fan, Qiuxiao Yu, Xiao Jia, Yu Sun, Wenpei Bai and Jihong Kang

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Oncotarget. 2018; 9:11905-11921. https://doi.org/10.18632/oncotarget.24190

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Xi Song1,*, Qiyang Shen1,*, Liting Fan1, Qiuxiao Yu1, Xiao Jia2, Yu Sun3, Wenpei Bai3 and Jihong Kang1

1Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China

2 Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China

3 Department of Obstetrics and Gynecology, Beijing Shijitan Hospital, Beijing, China

*These authors contributed equally to this work

Correspondence to:

Jihong Kang, email: [email protected]

Keywords: polycystic ovary syndrome (PCOS); dehydroepiandrosterone (DHEA); mTOR; autophagy; skeletal muscle insulin resistance

Received: July 18, 2017     Accepted: December 04, 2017     Published: January 12, 2018


Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age and also an important metabolic disorder associated with insulin resistance (IR). Hyperandrogenism is a key feature of PCOS. However, whether hyperandrogenism can cause IR in PCOS remains largely unknown. The mammalian target of rapamycin complex 1 (mTORC1) and its regulated autophagy are closely associated with IR. In the present study, we investigated the role of mTORC1-autophagy pathway in skeletal muscle IR in a dehydroepiandrosterone (DHEA)-induced PCOS mouse model. DHEA-treated mice exhibited whole-body and skeletal muscle IR, along with the activated mTORC1, repressed autophagy, impaired mitochondria, and reduced plasma membrane glucose transporter 4 (GLUT4) expression in skeletal muscle of the mice. In cultured C2C12 myotubes, treatment with high dose testosterone activated mTORC1, reduced autophagy, impaired mitochondria, decreased insulin-stimulated glucose uptake, and induced IR. Inhibition of mTORC1 or induction of autophagy restored mitochondrial function, up-regulated insulin-stimulated glucose uptake, and increased insulin sensitivity. On the contrary, inhibition of autophagy exacerbated testosterone-induced impairment. Our findings suggest that the mTORC1-autophagy pathway might contribute to androgen excess-induced skeletal muscle IR in prepubertal female mice by impairing mitochondrial function and reducing insulin-stimulated glucose uptake. These data would help understanding the role of hyperandrogenism and the underlying mechanism in the pathogenesis of skeletal muscle IR in PCOS.

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