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 1, * , Qiyang Shen 1, * , Liting Fan 1 , Qiuxiao Yu 1 , Xiao Jia 2 , Yu Sun 3 , Wenpei Bai 3 and Jihong Kang 1 1 Department 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: kangjihong@bjmu.edu.cn 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 ABSTRACT 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.