Augmentation of scleral glycolysis promotes myopia through histone lactylation.

Myopia is characterized of maladaptive increases in scleral fibroblast-to-myofibroblast transdifferentiation (FMT). Scleral hypoxia is a significant factor contributing to myopia, but how hypoxia induces myopia is poorly understood. Here, we showed that myopia in mice and guinea pigs was associated with hypoxia-induced increases in key glycolytic enzymes expression and lactate levels in the sclera. Promotion of scleral glycolysis or lactate production induced FMT and myopia; conversely, suppression of glycolysis or lactate production eliminated or inhibited FMT and myopia. Mechanistically, 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. Collectively, we suggest that scleral glycolysis contributes to myopia by promoting FMT via lactate-induced histone lactylation.

Hypoxia-Induced Scleral HIF-2α Upregulation Contributes to Rises in MMP-2 Expression and Myopia Development in Mice.

Purpose: Scleral hypoxia is a key factor that induces hypoxia-inducible factor-1α (HIF-1α) upregulation, and this response contributes to myopia progression. Currently, we aim to determine if the different HIF subtypes, including HIF-1α and HIF-2α, mediate hypoxia-induced myopia development through promoting scleral MMP-2 expression and collagen degradation. Methods: Our study included: (1) time-course of scleral HIF-2α, MMP-2, and COL1α1 expression during form-deprivation myopia (FDM) development was determined in C57BL/6J mice. (2) The effect of silencing either HIF-1Α or HIF-2A on hypoxia-induced alterations in MMP-2 expression was analyzed in cultured human scleral fibroblasts (HSFs) under a hypoxic condition (i.e. 1% oxygen). (3) To knock-down either HIF-1α or HIF-2α expression in the sclera, we performed Sub-Tenon's capsule injection of an adeno-associated virus (AAV)8-packaged Cre overexpression vector (AAV8-Cre) in HIF-1αfl/fl or HIF-2αfl/fl mice. HIF-1α, HIF-2α, MMP-2, and COL1α1 expression were analyzed by Western blot or quantitative real-time PCR (qRT-PCR). In addition, the effects of scleral HIF-2α knock-down on normal refractive development and FDM development were evaluated. Results: The time-dependent increases in scleral HIF-2α mimicked the HIF-1α expression profiles as we previously described. Hypoxia significantly promoted MMP-2 expression in HSFs, and this upregulation was solely alleviated by HIF-2A rather than HIF-1A silencing. Scleral HIF-2α knockdown significantly inhibited form-deprivation (FD)-induced MMP-2 upregulation and declines in COL1α1 accumulation and myopia development. Although scleral HIF-1α knockdown also significantly suppressed FD-induced declines in COL1α1 accumulation, it did not abrogate scleral MMP-2 upregulation. Conclusions: HIF-2α rather than HIF-1α induces myopia development through upregulating MMP-2 and promoting collagen degradation in the sclera.