SEARCHOTHERophthalmology, retina

other·ophthalmology, retina, nutrition, public health, animal science·PMC10036398

Voluntary exercise modulates pathways associated with amelioration of retinal degenerative diseases

Frontiers in Physiology · 11 authors, 4 centres

AI SUMMARY

FIDELITY 100%

POPULATIONAdult male and female C57BL/6J wild-type mice (aged P50 at onset)

INTERVENTIONVoluntary exercise via free access to running wheels for 28 days

COMPARISONSedentary mice (no running wheels) under same housing conditions

This summary was generated by AI from a single paper. It has not been reviewed by a clinician and is not clinical advice. Verify against the source before acting on it.

AGENT 01 · STRUCTURED SUMMARY

TRACE TO SOURCE

“

TL;DR

Voluntary exercise in mice for 28 days prior to photo-oxidative damage significantly preserved retinal function and morphology, reduced photoreceptor cell death and microglial/macrophage activation, and shifted retinal gene expression toward a healthy phenotype. Key modulated pathways included inflammation (complement, NLRP3) and extracellular matrix integrity. These findings support exercise as a non-pharmacological intervention to slow retinal degeneration, such as age-related macular degeneration.

Full summary

3,273 CHARS

**Background:** Physical activity is known to benefit central nervous system health, and emerging evidence suggests exercise protects against retinal degenerations including age-related macular degeneration (AMD). However, the molecular mechanisms underlying exercise-induced retinal protection remain poorly understood. This study aimed to investigate the effects of voluntary exercise on retinal degeneration using a mouse model of photo-oxidative damage (PD) that recapitulates key inflammatory aspects of AMD.

**Methods:** Adult C57BL/6J mice (P50) were housed individually with (exercise) or without (sedentary) free-access running wheels for 28 days. After the exercise period, mice were exposed to 5 days of PD (100 k lux white light). Retinal function was assessed by full-field scotopic electroretinography (ERG). Retinal morphology was evaluated using optical coherence tomography (OCT) and fundoscopy. Photoreceptor cell death was quantified by TUNEL assay, and retinal inflammation by IBA1 immunohistochemistry. Bulk RNA sequencing was performed on retinal lysates, followed by modular gene co-expression analysis and gene set enrichment analysis.

**Key Results:** Exercised mice ran an average of 10.2 km/day (SEM 1.84) and 257 min/day (SEM 24.3). Compared to sedentary controls, exercised mice showed significantly improved retinal function: a-wave (photoreceptor) and b-wave (second-order neuron) amplitudes were higher (p < 0.05). OCT revealed larger lesion-free retinal areas in exercised mice (39.7% ± 6.84%) vs. sedentary (17.4% ± 2.42%) (p < 0.05). Outer nuclear layer (ONL) thickness was greater in exercised mice (26.7 ± 1.73 μm) vs. sedentary (12.4 ± 0.99 μm) (p < 0.05). TUNEL+ cells were significantly reduced in exercised mice (p < 0.05), and photoreceptor nuclei rows were increased (p < 0.05). IBA1+ microglia/macrophages in the ONL were significantly fewer in exercised mice (p < 0.05), with reductions in both ramified and amoeboid morphologies. RNA sequencing showed that exercised mice had a transcriptomic profile closer to healthy (dim-reared) controls, with Euclidean distances significantly shorter (ED_dim-active = 20.2 ± 0.21 vs. ED_dim-sedentary = 24.5 ± 0.47, p < 0.05). Modular co-expression analysis identified six gene modules; modules M5 and M6 were downregulated in exercised mice and associated with inflammatory pathways (complement activation, NLRP3 inflammasome, microglial migration) and extracellular matrix (ECM) integrity pathways. Key downregulated genes included C3, C1q, Cx3CR1, Cd74, Itgam (Cd11b), and Timp3.

**Clinical Implications:** This study provides the first comprehensive molecular characterization of voluntary exercise-induced retinal protection, demonstrating that exercise dampens inflammatory pathways and preserves ECM integrity, shifting the retinal transcriptome toward a healthy phenotype. These findings support the potential of exercise as a non-pharmacological intervention to slow retinal degeneration, particularly AMD. The identification of specific pathways (complement, NLRP3, ECM) offers targets for future therapeutic development. The use of a voluntary exercise model more closely mimics clinical exercise regimens and avoids confounding stress effects seen in forced-exercise models.

PICO

PPOPULATION

Adult male and female C57BL/6J wild-type mice (aged P50 at onset)

IINTERVENTION

Voluntary exercise via free access to running wheels for 28 days

OOUTCOME

Retinal function (a-wave and b-wave amplitudes via ERG), retinal morphology (ONL thickness, lesion-free area), photoreceptor cell death (TUNEL+ cells), inflammation (IBA1+ microglia/macrophages), and retinal transcriptome (RNA-seq)

STUDY TYPE

other

SPECIALTY

ophthalmology

SUMMARISED BY

AI pipeline

FIDELITY CHECK

100% · A

ORIGINAL PAPER

PMC10036398

Voluntary exercise modulates pathways associated with amelioration of retinal degenerative diseases

Frontiers in Physiology

READ THE FULL PAPER

JUMP TO SECTION

ABSTRACT

Abstract Background: Exercise has been shown to promote a healthier and longer life and linked to a reduced risk of developing neurodegenerative diseases including retinal degenerations. However, the molecular pathways underpinning exercise-induced cellular protection are not well understood. In this work we aim to profile the molecular changes underlying exercise-induced retinal protection and investigate how exercise-induced inflammatory pathway modulation may slow the progression of retinal degenerations. Methods: Female C57Bl/6J mice at 6 weeks old were given free access to open voluntary running wheels for a period of 28 days and then subjected to 5 days of photo-oxidative damage (PD)-induced retinal degeneration. Following, retinal function (electroretinography; ERG), morphology (optical coherence tomography; OCT) and measures of cell death (TUNEL) and inflammation (IBA1) were analysed and compared to sedentary controls. To decipher global gene expression changes as a result of voluntary exercise, RNA sequencing and pathway and modular gene co-expression analyses were performed on retinal lysates of exercised and sedentary mice that were subjected to PD, as well as healthy dim-reared controls. Results: Following 5 days of PD, exercised mice had significantly preserved retinal function, integrity and reduced levels of retinal cell death and inflammation, compared to sedentary controls. In response to voluntary exercise, inflammatory and extracellular matrix integrity pathways were significantly modulated, with the gene expression profile of exercised mice more closely trending towards that of a healthy dim-reared retina. Conclusion: We suggest that voluntary exercise may mediate retinal protection by influencing key pathways involved in regulating retinal health and shifting the transcriptomic profile to a healthy phenotype. Keywords: retina, exercise, inflammation, retinal degeneration, cellular protection, age-related macular degeneration

CITATION EXPORT

Joshua A Chu-Tan, Adrian V Cioanca, Yvette Wooff et al.. Voluntary exercise modulates pathways associated with amelioration of retinal degenerative diseases. Frontiers in Physiology. (2023). https://doi.org/10.3389/fphys.2023.1116898

AUTHORS

11 · 4 CENTRES

Joshua A Chu-Tan, Adrian V Cioanca, Yvette Wooff, Max Kirkby, Marissa Ellis, Pranay Gulati, Tim Karl, Jeffrey H Boatright, Katie Bales, John Nickerson, Riccardo Natoli

1 Eccles Institute of Neuroscience, John Curtin School of Medical Research, College of Health and Medicine, The Australian National University, Acton, ACT, Australia
2 School of Medicine and Psychology, College of Health and Medicine, The Australian National University, Acton, ACT, Australia
3 School of Medicine, Western Sydney University, Penrith, NSW, Australia
4 Department of Ophthalmology, Emory University, Atlanta, GA, United States