# Genetic depletion of early autophagy protein ATG13 impairs mitochondrial energy metabolism, augments oxidative stress, induces the polarization of macrophages to M1 inflammatory mode, and compromises myelin integrity in skeletal muscle

## TL;DR

Reducing ATG13, an early autophagy protein, disrupts mitochondrial function, increases inflammation, and weakens muscle myelin, contributing to post-exertional malaise.

## Contribution

This study reveals a novel role for ATG13 in regulating macrophage polarization and mitochondrial metabolism through autophagy disruption.

## Key findings

- ATG13 depletion impairs mitochondrial oxidative metabolism and increases ROS in macrophages.
- Reduced ATG13 leads to M1 macrophage polarization and increased inflammatory markers.
- ATG13 ablation causes myelin deterioration and reduced muscle strength after exercise.

## Abstract

M1 macrophage activation is crucial in chronic inflammatory diseases, yet its molecular mechanism is unclear. Our study shows that hemizygous deletion of early autophagy gene atg13 (Tg+/−ATG13) disrupts cellular autophagy, hinders mitochondrial oxidative metabolism, increases reactive oxygen species (ROS) in splenic macrophages, leading to its M1 polarization. Reduced macroautophagy markers WDFY3 and LC3, flow-cytometric analysis of M1/M2 markers (CD40, CD86, CD115, CD163, and CD206), deficit of oxygen metabolism evaluated by ROS-sensor dye DCFDA, and seahorse oxygen consumption studies revealed that atg13 gene ablation impairs mitochondrial function triggering M1 polarization. Additionally, redox imbalance may impair Sirtuin-1 activity via nitrosylation, increasing the level of acetylated p65 in macrophages contributing to the inflammatory response in M1Mφ. Additionally, the ablation of the atg13 gene resulted in the increased infiltration of M1Mφ in muscle vasculature, deterioration of myelin integrity in nerve bundles, and a reduction in muscle strength following treadmill exercise. These findings underscore the significance of ATG13 in post-exertional malaise (PEM).