MicroRNA-34a targets sirtuin 1 and leads to diabetes-induced testicular apoptotic cell death.

Testicular apoptotic cell death (TACD) contributes to diabetes mellitus (DM)-induced male infertility. MicroRNA-34a (miR-34a) is a pro-apoptotic RNA that targets sirtuin 1 (SIRT1) which provides protection against complications of (DM). However, the specific role of miR-34a in (DM)-induced TACD is unknown. MiR-34a targets Sirt1 mRNA, resulting in apoptosis. However, whether or not SIRT1 is a major target of miR-34a in (DM)-induced TACD is unclear. The present study aimed to define the role of miR-34a/SIRT1 in (DM)-induced TACD. C57BL/6 male mice were induced to (DM) by streptozotocin, for a period of 24 weeks. The expression of miR-34a and Sirt1 as well as apoptotic cell death was determined in the testes of the non-diabetic, diabetic, and the miR-34a-specific inhibitor (miR-34a-I)-treated diabetic mice. In addition, the novel SIRT1 activator SRT2104 was delivered to the mice to determine the role of SIRT1 in DM-induced TACD. The diabetic mice developed remarkable testicular oxidative stress, endoplasmic reticulum stress, and apoptotic cell death, the effects of which were significantly and similarly attenuated by both miR-34a-I and SRT2104. Mechanistically, the DM-induced testicular elevation of miR-34a and the decrease in SIRT1 protein were markedly prevented by both miR-34a-I and SRT2104, to a similar extent. The present study demonstrates a critical role of miR-34a/SIRT1 in DM-induced TACD, providing miR-34a inhibition and SIRT1 activation as novel strategies in clinical management of DM-induced male infertility.

KEY MESSAGES: MiR-34a mediates diabetes-induced TACD via inhibition of SIRT1. The novel SIRT1 activator SRT2104 attenuates diabetes-induced TACD. MiR-34a inhibition activates SIRT1 and prevents diabetes-induced TACD.