SIRT1 alleviates hypoxia-induced mitochondrial dysfunction and scleral remodeling in scleral fibroblasts by regulating AMPK via FOXO1.

Background

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Purpose

Myopia is a globally prevalent refractive error. Sirtuin 1 (SIRT1) may be involved in myopia progression, but the specific underlying mechanisms remain to be elucidated. This study aimed to investigate the role of SIRT1 in myopia and elucidate its underlying mechanisms.

Methods

A mouse myopia model was established using monocular form deprivation (FD), and human scleral fibroblasts (HSFs) were treated with 5% oxygen to simulate a hypoxic environment. The expression levels of key genes and proteins were detected via RT-qPCR, Western blotting, and immunohistochemistry. Refractive phenotype and scleral morphology of the eyeball were evaluated via diopter measurement, axial length detection and H&E staining. Mitochondrial function and oxidative stress levels were evaluated using DCFH-DA, JC-1 staining, and ATP assay kits. FOXO1 acetylation levels were assessed using an acetylation-specific antibody following immunoprecipitation of FOXO1.

Results

This study found that SIRT1 expression is downregulated in the scleral tissues of FD mice and in hypoxia-induced HSFs. SIRT1 overexpression enhanced mitochondrial function in hypoxia-exposed HSFs improved scleral mitochondrial function and ameliorated myopia progression in FD mice. Further research revealed that SIRT1 promotes FOXO1 deacetylation and nuclear translocation in HSFs, thereby activating the AMPK signaling pathway. In vitro, the effects of SIRT1 overexpression were attenuated by FOXO1 knockdown or treatment with the AMPK inhibitor dorsomorphin, leading to weakened mitochondrial function in HSFs under hypoxic conditions.

Conclusion

SIRT1 promotes the deacetylation and nuclear translocation of FOXO1 and further activates the AMPK pathway, thereby ameliorating hypoxia-induced mitochondrial dysfunction and cellular damage in scleral fibroblasts and delaying myopia progression in FD mice.