Abstract
Purpose :
We showed previously that hypoxia contributed to myopia by promoting scleral fibroblast-to-myofibroblast transdifferentiation (FMT). Hypoxia is one of the most important stimulators of glycolytic reprogramming and lactate production. Recent findings suggest that lactate-derived histone lactylation is involved in many diseases. We set out to investigate whether scleral glycolytic reprogramming and histone lactylation might be contributory factors to myopia.
Methods :
Our study included: 1) Time-course of scleral levels of the glycolytic rate-limiting enzymes protein, lactate, and histone lactylation, during form-deprivation myopia (FDM) development were determined in mice and guinea pigs. 2) Overexpression/Knock-down of PKM2 or LDHA was used to increase/decrease the glycolysis or lactate production in the sclera in mice, and its effect on normal refractive development or FDM was analyzed. 3) The effect of pharmacological suppression of scleral glycolysis or lactate production on FDM was assessed in guinea pigs. 4) In cultured human scleral fibroblasts, the effects of inhibition of glycolysis or lactate production on FMT was evaluated. 5) Genetic analyses of myopia GWAS data in UK biobank were performed to assess the association between glycolysis and human myopia. 6) The influence of a high sugar intake (HSD) on normal refractive development and FDM development was determined in guinea pigs.
Results :
Myopia in mice and guinea pigs was associated with hypoxia-induced increases in key glycolytic enzymes expression and lactate levels in sclera. Promotion of scleral glycolysis or lactate production induced FMT and myopia; conversely, genetic or pharmacological inhibition of glycolysis or lactate production eliminated or inhibited FMT and myopia. Increasing scleral glycolysis-lactate levels promoted FMT and myopia via H3K18la and this promoted Notch1 expression. Genetic analyses identified a significant enrichment of two genes encoding glycolytic enzymes ENO2 and TPI1. Moreover, increasing sugar intake in guinea pigs not only induced myopia but also enhanced the response to myopia induction via the scleral glycolysis-lactate-histone lactylation pathway.
Conclusions :
We suggest that scleral glycolysis contributes to myopia by promoting FMT via lactate-induced histone lactylation. Restriction of dietary sugar levels might be a candidate for myopia control.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.