Inactivation of ATG13 stimulates chronic demyelinating pathologies in muscle-serving nerves and spinal cord.
Drosen, Molly E, Bulbule, Sarojini, Gottschalk, Gunnar et al. · Immunologic research · 2025 · DOI
Quick Summary
Researchers gave mice a drug that overactivates a protein called mTOR and found it triggered muscle weakness, nerve damage, and worsening fatigue after exercise—similar to post-exertional malaise (PEM) in ME/CFS. The drug blocked a cellular cleanup system called autophagy, which led to inflammation and damage to the nerves controlling muscles. Mice engineered to have impaired autophagy showed similar problems, suggesting that broken autophagy may be involved in ME/CFS fatigue and exercise intolerance.
Why It Matters
This study identifies a potential molecular mechanism linking autophagy dysfunction to both chronic muscle weakness and post-exertional malaise—two hallmark features of ME/CFS. Understanding that mTOR hyperactivation may impair cellular cleanup and trigger demyelination and inflammation offers new targets for therapeutic intervention in ME/CFS patients.
Observed Findings
MHY1485-induced mTOR activation in mice caused severe muscle weakness and impaired exercise tolerance with worsened fatigue after treadmill exercise.
MHY1485 treatment impaired ATG13-dependent autophagy and increased infiltration of pro-inflammatory M1 macrophages.
MHY1485 feeding upregulated IL-6 and RANTES cytokines via STAT3 activation and caused demyelination of muscle-serving nerve fibers and spinal cord tracts.
ATG13-repressor transgenic mice exhibited similar pathology: M1 macrophage infiltration, STAT3 activation, demyelination, and PEM-like symptoms after exercise.
Inferred Conclusions
Chronic mTOR activation impairs ATG13-dependent autophagy, leading to inflammatory and demyelinating pathology in motor nerves and spinal cord.
mTOR hyperactivation and autophagy dysfunction may contribute to post-exertional malaise pathogenesis in chronic fatigue conditions.
ATG13 impairment is a critical mechanism linking autophagy failure to demyelination, inflammation, and exercise-induced fatigue exacerbation.
Remaining Questions
Is mTOR hyperactivation or ATG13 dysfunction present in peripheral blood, nerve tissue, or cerebrospinal fluid of ME/CFS patients?
Do mTOR inhibitors or autophagy enhancers reverse demyelination and PEM-like symptoms in these mouse models?
What This Study Does Not Prove
This study does not prove that mTOR hyperactivation or ATG13 impairment occurs in human ME/CFS patients; these are animal models that may not fully recapitulate the human disease. It also does not establish causality in humans or rule out other contributing genetic and environmental factors in ME/CFS pathogenesis. Results in mice do not guarantee efficacy or safety of mTOR-targeting treatments in clinical practice.
About the PEM badge: “PEM required” means post-exertional malaise was an explicit required diagnostic criterion for participant inclusion in this study — not that PEM was studied, observed, or discussed. Studies using criteria that do not require PEM (e.g. Fukuda, Oxford) are tagged “PEM not required”. How the atlas works →