# Aerobic exercise training attenuates cardiac inflammation and fibrosis in mice with type 2 diabetes and inhibits the advanced glycation end products pathway

## TL;DR

Aerobic exercise reduces heart inflammation and fibrosis in diabetic mice by targeting the AGE signaling pathway.

## Contribution

This study shows that aerobic exercise specifically downregulates the AGE pathway and reduces cardiac damage in T2D mice.

## Key findings

- Aerobic exercise reduced cardiac AGE deposition and RAGE expression in T2D mice.
- Exercise suppressed cardiac inflammation and fibrosis by decreasing IL-6, TNF-α, and NF-kB.
- AGE pathway components correlated strongly with fibrosis, inflammation, and oxidative stress markers.

## Abstract

Type 2 diabetes mellitus (T2D) is associated with cardiac dysfunction caused by oxidative stress, inflammation, and fibrosis. Exercise has shown cardioprotective effects in T2D. However, the impact on the Advanced Glycation End Products (AGE) and its receptors remains unclear. In this study, we investigated whether aerobic exercise modulates the AGE signaling pathway in the hearts of diabetic mice and whether it is associated with oxidative and inflammatory damage.

Male C57BL/6 mice were fed a control (CTL) diet or a high-fat, high-carbohydrate (HFHC) diet to induce T2D. A subset of the T2D mice underwent aerobic training for 12 weeks (T2D EX), whereas the other mice remained sedentary (T2D). Cardiac tissues were analyzed for AGE deposition, AGE receptors expression, oxidative stress markers, cytokine profiles, and histological changes, including fibrosis and inflammation.

Aerobic exercise in T2D mice reduced the cardiac deposition of fluorescent AGEs and CML, decreased RAGE protein and gene expression, downregulated CD36 and galectin-3 receptors, while not affecting GLO-1 detoxification system. Exercise in T2D mice suppressed cardiac inflammation and fibrosis. Improvements in inflammatory profiles included reduced expression of IL-6, TNF-α, and NF-kB. However, markers of oxidative stress, such as malondialdehyde, remained largely unaffected by exercise. Pearson’s correlation analysis showed strong associations between AGE signaling pathway components and cardiac fibrosis, inflammation, and oxidative stress parameters.

Aerobic exercise mitigates cardiac changes in T2D by downregulating the AGE signaling pathway and reducing fibrosis and inflammation. These findings highlight the therapeutic potential of exercise in interfering with AGE-mediated mechanisms to alleviate T2D-associated cardiovascular complications.

The online version contains supplementary material available at 10.1186/s13098-025-02076-x.