Wheel running exercise protects against retinal degeneration in the I307N rhodopsin mouse model of inducible autosomal dominant retinitis pigmentosa

• Published in: Molecular vision 2019, Vol.25, p.462-476
• Main Authors: Zhang, Xian, Girardot, Preston E, Sellers, Jana T, Li, Ying, Wang, Jiaxing, Chrenek, Micah A, Wu, Wenfei, Skelton, Henry, Nickerson, John M, Pardue, Machelle T, Boatright, Jeffrey H
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Apoptosis; Atropine; Cell membranes; Cell size; Cytology; Cytosol; Disease Models, Animal; DNA nucleotidylexotransferase; Electroretinograms; Genes, Dominant; Hereditary diseases; Inflammation; Inflammation - pathology; Mice, Inbred C57BL; Morphology; Mutation - genetics; Optomotor response; Paraffin; Phenotypes; Photoreceptor Cells, Vertebrate - metabolism; Photoreceptor Cells, Vertebrate - pathology; Photoreceptors; Physical Conditioning, Animal; Physical training; Retina; Retinal Degeneration - genetics; Retinal Degeneration - physiopathology; Retinal Degeneration - prevention & control; Retinal Pigment Epithelium - pathology; Retinal Pigment Epithelium - physiopathology; Retinitis; Retinitis pigmentosa; Retinitis Pigmentosa - genetics; Retinitis Pigmentosa - physiopathology; Rhodopsin - genetics; Vision, Ocular; Visual perception; Wheel running; α-Catenin
• ISSN: 1090-0535; 1090-0535

We previously reported that modest running exercise protects photoreceptors in mice undergoing light-induced retinal degeneration and in the rd10 mouse model of autosomal recessive retinitis pigmentosa (arRP). We hypothesized that exercise would protect against other types of retinal degeneration, specifically, in autosomal dominant inherited disease. We tested whether voluntary running wheel exercise is protective in a retinal degeneration mouse model of class B1 autosomal dominant RP (adRP). C57BL/6J mice heterozygous for the mutation in I307N rhodopsin ( ) (also known as RHO , or Tvrm4) are normal until exposed to brief but bright light, whereupon rod photoreceptor degeneration ensues. I307N mice were given access to free spinning (active) or locked (inactive) running wheels. Five weeks later, half of each cohort was treated with 0.2% atropine eye drops and exposed to white LED light (6,000 lux) for 5 min, then returned to maintenance housing with wheels. At 1 week or 4 weeks after induction, retinal and visual function was assessed with electroretinogram (ERG) and optomotor response (OMR). In vivo retinal morphology was assessed with optical coherence tomography (OCT), and fundus blue autofluorescence assessed using a scanning laser ophthalmoscope. The mice were then euthanized, and the eyes fixed for paraffin sectioning or flatmounting. The paraffin sections were stained with hematoxylin and eosin (H&E) and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) to assess retina morphology and apoptosis. Half of the 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 RPE cell stress.) The remaining flatmounts were stained for ZO-1 and Iba-1 to assess the RPE cell size and shape, and inflammatory responses. In vivo measures revealed that induction of the I307N degeneration decreased retinal and visual function, decreased the thickness of the retina and photoreceptor layers, and increased the number of blue autofluorescence spots at the level of the photoreceptor-RPE interface. Post-mortem analyses showed that induction caused loss of photoreceptors in the central retinal region, and increased TUNEL labeling in the outer nuclear layer (ONL). The RPE was disrupted 1 week after induction, with changes in cell size and shape accompanied by increased α-catenin translocation and Iba-1 staining. These outcomes