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.

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).