Abstract
Purpose :
Ketogenic diet has been used to alleviate degeneration in glaucoma models, and elevates expression of monocarboxylate transporter-2 (MCT-2), the means by which axons in the optic nerve import lactate, pyruvate, and ketone bodies for metabolic support. We tested the effect on retinal ganglion cell (RGC) survival of increasing MCT-2 expression, seeking to determine if MCT-2 elevation is sufficient to protect RGCs in glaucoma.
Methods :
The DBA-2J mouse and microbead occlusion models of glaucoma were injected with AAV2-CAG2-mSLC16A7-2A-GFP to infect RGCs and upregulate MCT-2 expression in the retina. Optic nerve (ON) axons stained with PPD and RGC somas immunolabeled with RBPMS were quantified in glaucoma and control (DBA/2-Gpnmb+ or sham injection) groups. MCT-2, AMPK, and PGC-1α proteins were quantified using capillary electrophoresis. Pattern electroretinogram (PERG) was measured to assess retinal function.
Results :
MCT-2 elevation by AAV2 infection rescued RGCs in glaucomic conditions. AAV2 injected mice had significantly higher ON axon number (n=27, p<0.0001), and significantly higher numbers of RGC somas in retina (n=37 p<0.0001) than did untreated glaucomic mice. Phosphorylated AMPK was downregulated in AAV2-MCT2 mice compared to untreated glaucomic mice (p<0.0001), suggesting restoration of balanced metabolic activity with AAV2-MCT2 treatment. PGC-1α, a mitochondrial biogenesis transcriptional coactivator, is expressed at significantly higher levels in AAV2-MCT2 glaucomic mice than in untreated mice (n=11 p=0.0034). PERG showed higher P1 amplitude in AAV2-MCT2 glaucomic mouse eyes as compared to untreated eyes.
Conclusions :
MCT-2 overexpression is associated with increased RGC survival in glaucomic models. This is consistent with our hypothesis that metabolic deficiencies in glaucoma are responsible in part for glaucomic degeneration. Further research into how best to support RGCs and ON axons metabolically may lead to future treatments of glaucoma.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.