Bmal1 deficiency disrupts autophagy-apoptosis equilibrium in a hyperandrogenic PCOS-like rat model.

RESEARCH QUESTION: Does the circadian rhythm gene Bmal1 play a role in regulating autophagy, apoptosis and follicular development in polycystic ovary syndrome (PCOS)?

DESIGN

To investigate the role of Bmal1 in PCOS, a PCOS-like rat model was established using letrozole treatment combined with a high-fat diet and a testosterone-treated human granulosa tumour cell line (KGN cell) model. Oestrous cycles were monitored in control rats and the PCOS-like model. Post-experiment analyses included body weight, hormone concentrations, histopathological and immunohistochemical assessments, and evaluation of autophagy and apoptosis markers. In vitro, KGN cells were treated with testosterone to mimic the hyperandrogenic environment of PCOS, and Bmal1 expression was manipulated to study its effects on autophagy and apoptosis.

RESULTS

Bmal1 expression in ovarian tissue of PCOS-like rats was reduced significantly compared with the control group (P = 0.0016), accompanied by increased levels of autophagy and apoptosis. In-vitro experiments demonstrated that Bmal1 knockdown and testosterone-treated KGN cells exhibited similar patterns of elevated autophagy and apoptosis. Notably, Bmal1 expression decreased in KGN cells exposed to testosterone (P = 0.0383), indicating that elevated androgen concentrations in the PCOS environment suppress Bmal1, thereby promoting autophagy and apoptosis in granulosa cells.

CONCLUSION

These findings suggest that Bmal1 plays a critical role in regulating autophagy and apoptosis in granulosa cells, and its suppression by elevated androgen concentrations contributes to abnormal follicular development in PCOS. These results suggest the potential of targeting Bmal1 and circadian rhythm pathways as a novel therapeutic strategy for PCOS.