# ATG13: A new player in ME/CFS

> **NIH NIH R21** · SIMMARON RESEARCH INC · 2024 · $225,000

## Abstract

Project summary: Myalgic encephalomyelitis and chronic fatigue syndrome (ME/CFS) is a multisystem
chronic illness characterized by extreme fatigue, muscle weakness, muscle pain, dizziness, a cognitive deficit of
attention, and depression. Despite intense investigation, the molecular mechanism of this disease is still
unknown. Our recent finding suggests that the functional inactivation of ATG13, an essential protein of cellular
autophagy, contributes to the pathogenesis of ME/CFS. To further characterize the role of ATG13 in the
pathogenesis of ME/CFS, a reliable disease model is required that exhibits some of the cardinal disease
symptoms such as post-exertional malaise (PEM) and orthostatic intolerance (OI). PEM is characterized by
severe muscle fatigue and pains immediately after exercise, whereas OI is characterized by the sudden drop in
blood pressure in an upright condition. Our preliminary results suggest that MHY1485, an agonist of mammalian
target of rapamycin (mTOR), inactivates ATG13-dependent autophagy and induces severe fatigue and PEM in
3-4 weeks old female mice. Therefore, to establish the direct role of Atg13 in ME/CFS pathogenesis, our overall
hypothesis is that atg13 depletion will display a spontaneous PEM pathology. In aim1, we will generate a
mouse strain with muscle-specific knock-out of the atg13 gene (atg13∆muscle). A 20-minute acute treadmill running
protocol and 2-days CPET tests would be adopted in these mice followed by simultaneous measurement of M-
wave amplitude through EMG recording, decreased mobility recorded by Stoelting ANY-maze tracking software,
muscle pain, stress, and neurocognitive impairment of attention (Aim 1.1). Molecular analysis of mitochondrial
impairment in energy metabolism, calcium homeostasis, apoptosis, and anaerobic glycolysis would be evaluated
in these mice (Aim 1.2). Under aim2, we would see if neural mutation of atg13 in myelinating cells of the brain
(atg13∆brain) or ablation of atg13 in sensory neurons (atg13∆PNS) contributes to the pathogenesis of ME/CFS such
as autonomic dysfunction, the cognitive deficit of attention, anxiety, and pain. Briefly, atg13∆brain and atg13∆PNS
mice would be generated and then analyzed for chronic fatigue, followed by a 2-Days CPET test. After another
3-4 weeks, muscle fatigue, pain, stress, and neurocognitive impairment (aim 2.1) would be evaluated. Since
chronic inflammation is one of the cardinal symptoms of ME/CFS, we would assess peripheral inflammation of
CD4 Th1 cell activation in the spleen- and lymph node-derived mononuclear cells (Aim 2.2). Central inflammation
will be assessed by monitoring the activation of NF-κB, iNOS, and RANTES production in the brain and spinal
cord (Aim 2.2). If successful, our current proposal identifies the first mouse model to study ME/CFS and ME/CFS-
associated PEM.

## Key facts

- **NIH application ID:** 10833667
- **Project number:** 5R21NS129021-02
- **Recipient organization:** SIMMARON RESEARCH INC
- **Principal Investigator:** AVIK ROY
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $225,000
- **Award type:** 5
- **Project period:** 2023-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10833667

## Citation

> US National Institutes of Health, RePORTER application 10833667, ATG13: A new player in ME/CFS (5R21NS129021-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10833667. Licensed CC0.

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