Toriola et al. (2025)
- Authors: Mubaraq A. Toriola, Emma Timlin, Sarojini Bulbule, Amy Reyes, Omolola Mary Adedeji, C. Gunnar Gottschalk, Animesh Barua, Leggy A. Arnold, Avik Roy
- Institutes: University of Wisconsin-Milwaukee; Simmaron Research INC.
- Publisher: Research Square
- Link: DOI
Summary
This research provides a potential biological mechanism that connects impaired cellular “housekeeping” (autophagy) to the mitochondrial dysfunction, immune activation, and post-exertional malaise seen in ME/CFS. By using a mouse model, the study demonstrates how a single genetic defect can cause immune cells to become inflammatory, leading them to infiltrate muscles, damage local nerves, and cause profound weakness that worsens after exertion. This work strengthens the evidence for the roles of autophagy and mitochondrial health in ME/CFS and suggests that targeting these pathways could be a future therapeutic strategy.
What was researched?
This study investigated the molecular consequences of genetically reducing ATG13, a key protein involved in autophagy (the cell’s quality control and recycling system). Using a mouse model, researchers explored how this depletion affects mitochondrial energy metabolism, inflammation in immune cells called macrophages, and the health of nerves within skeletal muscle, particularly in the context of post-exertional malaise (PEM).
Why was it researched?
Previous research showed that disrupting the atg13 gene in mice led to muscle weakness and nerve damage, but the underlying mechanism was unclear. Given that ME/CFS is characterized by PEM, mitochondrial dysfunction, and immune abnormalities, the researchers hypothesized that studying the effects of ATG13 depletion could provide a relevant animal model to better understand the molecular basis of the disease.
How was it researched?
This was a preclinical study using a genetically engineered mouse model with a partial deletion of the atg13 gene (). Researchers compared these mice to normal mice by isolating macrophages from their spleens and analyzing them with multiple lab techniques. They used seahorse assays to measure mitochondrial oxygen consumption and glycolysis, flow cytometry to determine the polarization of macrophages into pro-inflammatory (M1) or anti-inflammatory (M2) types, and immunofluorescence to visualize proteins in tissue. Muscle function and fatigue were assessed using open-field behavioral tests and EMG recordings before and after a treadmill exercise challenge.
What has been found?
The study found that reducing ATG13 impaired autophagy, leading to mitochondrial dysfunction in macrophages, characterized by reduced ATP production and increased reactive oxygen species (ROS). This metabolic defect caused the macrophages to shift to a pro-inflammatory M1 state. These inflammatory M1 macrophages were found to infiltrate the blood vessels in skeletal muscle, which was associated with damage to the myelin sheath of muscle-serving nerves. Critically, these energy metabolism deficits and the resulting muscle weakness were significantly exacerbated following a treadmill exercise challenge, mirroring the PEM experienced by patients.
Discussion
The authors propose a novel mechanism where impaired autophagy, caused by ATG13 depletion, triggers a cascade of pathological events relevant to ME/CFS. They suggest that the resulting mitochondrial dysfunction and oxidative stress lead to reduced activity of the deacetylase enzyme SIRT1, which in turn promotes a pro-inflammatory state via activation of NF-κB. This model connects the dots between a fundamental cellular process (autophagy), immune cell dysfunction (M1 polarization), and key symptoms like muscle fatigue and PEM.
Conclusion & Future Work
The authors conclude that the genetic depletion of ATG13 creates a robust model for inflammation-driven muscle fatigue, linking impaired autophagy to mitochondrial deficits, M1 macrophage polarization, and nerve demyelination. Their future work will involve studying M1/M2 polarization in immune cells derived from ME/CFS patients participating in a clinical trial of the mTOR inhibitor rapamycin 💊, aiming to translate these findings from the mouse model to human patients.