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PDE5A Suppresses Proteasome Activity Leading to Insulin Resistance in C2C12 Myotubes
Author(s) -
Wei Liu,
Xiaojun Tian,
Wu Ti,
Le Liu,
Yanghongyun Guo,
Changhua Wang
Publication year - 2019
Publication title -
international journal of endocrinology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.875
H-Index - 60
eISSN - 1687-8345
pISSN - 1687-8337
DOI - 10.1155/2019/3054820
Subject(s) - myogenesis , medicine , insulin resistance , protein kinase b , endocrinology , proteasome , insulin , c2c12 , insulin receptor , biology , microbiology and biotechnology , myocyte , signal transduction
Objective The involvement of phosphodiesterase type 5 (PDE5) in the development of insulin resistance has been reported recently. However, the underlying molecular mechanism remains unclear. The present study aims at investigating the potential impacts of PDE5A on insulin signaling in C2C12 skeletal muscle myotubes and uncover the related mechanism.Methods C2C12 myoblasts were differentiated into myotubes. Western blot was performed to detect the levels of proteins and phosphorylated proteins. Glucose uptake was determined by a colorimetric kit. The overexpression or knockdown of specific protein was carried out by infecting the myotubes with adenoviruses carrying cDNA or shRNA corresponding to the targeted protein, respectively.Results PDE5A was demonstrated to negatively regulate insulin signaling, evidenced by the opposite effects on the suppression or enhancement of the insulin-stimulated Akt phosphorylation and 2-deoxy-D-glucose (2-DG) uptake in C2C12 myotubes, when PDE5A was overexpressed or knockdown, respectively. Interestingly, PDE5A overexpression led to significantly enhanced, while its knockdown resulted in markedly reduced, endoplasmic reticulum (ER) stress. Inhibition of ER stress improved PDE5A overexpression-induced insulin resistance. In addition, PDE5A was found to suppress proteasome activity. Inhibition of PDE5 by its selective inhibitor icariin restored PDE5A overexpression-reduced proteasome activity and mitigated PDE5A overexpression-induced ER stress. Consistently, icariin administration also markedly attenuated the detrimental impacts of PDE5A overexpression on insulin signaling.Conclusions These results suggest that PDE5A suppresses proteasome activity, which results in ER stress and subsequent insulin resistance in C2C12 myotubes.

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