High-intensity interval training modulates retinal microvascular phenotype and DNA methylation of p66Shc gene: a randomized controlled trial (EXAMIN AGE)

Aims Impairments of retinal vessel diameter are associated with major adverse cardiovascular (CV) events. Promoter DNA methylation is a repressor of the mitochondria! adaptor p66(Shc) gene transcription, a key driver of ageing-induced reactive oxygen species. The study aimed to investigate whether high-intensity interval training (HIIT) affects retinal microvascular phenotype as well as p66(Shc) expression and oxidative stress in ageing subjects with increased CV risk from the EXAMIN AGE cohort. Methods and results Eighty-four sedentary subjects (mean age 59.4 +/- 7.0 years) with >= 2 CV risk factors were randomized into either a and 12-week HIIT or standard physical activity recommendations. Retinal arteriolar and venular diameters were measured by use of a retinal vessel analyser. As a marker of oxidative stress plasma 3-nitrotyrosine (3-NT) level was determined by ELISA. Gene expression of p66(Shc)` and DNA methylation were assessed in mononuclear cells by RT-qPCR and methylated-DNA capture (MethylMiner Enrichment Kit) coupled with qPCR, respectively. High-intensity interval training reduced body mass index, fat mass, low-density lipoprotein and increased muscle mass, as well as maximal oxygen uptake (VO(2)max). Moreover, HIIT restored microvascular phenotype by inducing retinal arteriolar widening (pre: 175 +/- 14 mu m vs. post: 181 +/- 131 mu m, P= 0.001) and venular narrowing (pre: 222 +/- 14 mu m vs. post: 220 +/- 14 mu m, P=0.007). After HIIT, restoration of p66(Shc) promoter methylation (P= 0.034) reduced p66(Shc) gene expression (P=0.037) and, in turn, blunted 3-NT plasma levels (P=0.002). Conclusion High-intensity interval training rescues microvascular dysfunction in ageing subjects at increased CV risk. Exercise- induced reprogramming of DNA methylation of p66(Shc) gene may represent a putative mechanistic link whereby exercise protects against age-related oxidative stress.