Exercise protects against retinal degeneration and retinal pigment epithelium (RPE) stress in the RHO^tvrm4/+ mouse model of retinitis pigmentosa

Abstract

Purpose : We find that modest running exercise protects photoreceptors in mouse models of retinal degeneration. Here we tested whether exercise similarly protects retinal pigment epithelium (RPE) cells undergoing stress observed weeks after activation of the RHO^tvrm4/+ model of retinal degeneration.

Methods : Adult male RHO^tvrm4/+ mice were given access to free spinning (active) or locked (inactive) running wheels. Two weeks later, half of each cohort was treated with 0.2% atropine eye drops and exposed to LED light (6,000 lux) for 5 minutes. Before light exposure and at 1 and 2 months after light exposure, optical coherence tomography (OCT), electroretinogram (ERG), and optomotor response (OMR) were assessed. Mice were then sacrificed and eyes fixed for flatmounting. Flatmounts were stained for ZO-1 and α-catenin to assess RPE cell structure and stress. (We previously reported that translocation of α-catenin from cell membranes into the cytosol indicates cell stress.)

Results : Activation of the RHO^tvrm4/+ degeneration decreased visual acuity, thickness of the photoreceptor layer, and visual function. Notably, increased α-catenin translocation was observed in RPE flatmounts. These outcomes were partially prevented in exercised mice. Visual acuity (assessed as spatial frequency in units of cycles/degree) was significantly decreased in induced mice (0.108±0.049) compared to uninduced mice (0.274±0.022); p=0.01 by one-way ANOVA test, but exercise prevented this loss (0.211±0.016), observed as no significant difference with uninduced animals. Whole retina and photoreceptor layers as measured by OCT were significantly thicker in induced animals that were exercised versus non-exercised (138.6±9.00 vs 102.5±5.10; p=0.006) and 44.98±9.47 vs 11.59±3.81; p=0.009, respectively). Exercised mice did not exhibit increased RPE α-catenin translocation. ERG amplitudes trended towards less functional loss in exercised animals.

Conclusions : Activated RHO^tvrm4/+ mice lose retinal and visual function, with concomitant changes in the morphology of the retina and RPE. Exercise significantly protects against this pathological process, observed as decreased RPE stress and better retinal and visual outcomes.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.