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Solve-Funded Research at Simmaron Finds New Animal Models to Study ME/CFS–Related Muscle Fatigue and PEM

Post-exertional malaise (PEM) is the most prominent and common symptom of ME/CFS, but researchers have struggled to fully understand why patients with ME/CFS have this symptom. An important roadblock is that researchers have lacked well-established models for doing experiments with animals to learn about post-exertional malaise. Animal experiments are especially critical for studying diseases like ME/CFS because we often lack enough tissue samples from humans to analyze. And drug-safety and -efficacy data from animal models are essential for testing treatments in clinical trials.

Dr. Avik Roy—chief scientific officer at the non-profit Simmaron Research Institute and professor at the University of Wisconsin–Milwaukee—has now described two new animal models to study muscle fatigue and PEM in people with ME/CFS. This paper, “Inactivation of ATG13 stimulates chronic demyelinating pathologies in muscle-serving nerves and spinal cord,” appeared in the journal Immunologic Research. Solve M.E. has long supported Dr. Avik Roy’s important work, awarding Dr. Roy a Ramsay Research Grant in 2022 and teaming up with Dr. Roy to launch a clinical trial for treating patients with ME/CFS and PEM this past year.

In earlier work using his Ramsay funds, Dr. Roy showed that a protein called MTOR (mammalian target of rapamycin) is hyperactive in some patients with ME/CFS. The hyperactive MTOR inhibited another protein called ATG13 (autophagy-related protein 13), important for autophagy. Autophagy is the process by which cells clear unwanted components, like damaged or unnecessary proteins or mitochondria. When autophagy levels are too low and these unwanted components accumulate, inflammation and dysfunctional immune responses may ensue. Indeed, in early-stage experiments with mice, the team found that mice with dysregulated autophagy were more fatigued after physical activity than were mice with normal autophagy. This suggested that the problems with autophagy contribute to post-exertional malaise.

In this most recent work, Dr. Roy’s team established two critical experimental mouse models to determine how MTOR, ATG13, and autophagy relate to PEM. In the first model, the team fed mice a chemical that hyper-stimulates MTOR, dysregulating autophagy. In the second model, the team genetically modified mice to inactivate ATG13, also dysregulating autophagy. The team then used these two models to see how dysregulated autophagy affected muscle fatigue and PEM.

They saw that the hyperactive MTOR and inactivated ATG13 strongly disrupted autophagy; significantly increased inflammation in muscle tissues (as seen by significant levels of inflammatory cytokines and immune cells in the muscles); and severely damaged nerves that originated from the spinal cord to innervate muscles. In both models, the mice (especially the female ones) had severe symptoms of muscle fatigue. Female mice had significant problems with mobility and grip strength; with the integrity and electrical activities of muscle-controlling nerves; and with muscle growth and muscle-cell survival. Importantly, after exercising on treadmill, the mice with dysregulated autophagy were significantly more fatigued than were the normal mice. The mice with autophagy problems could not physically recover even two days after exercising, while the normal mice recovered fully.

Dr. Roy’s study is vital because clinical trials may use these animal models to measure how pharmacological treatments (like those targeting MTOR or ATG13) may reduce PEM for patients with ME/CFS. Dr. Roy’s team is already using these models in clinical trials testing whether rapamycin (a drug that inhibits MTOR) reduces PEM in some patients. Their unpublished results from their phase 1 study are highly encouraging, and the team will soon launch a phase 2 trial. Solve is supporting these clinical trials by providing extra funds and by aiding in recruiting participants.

Importantly, these animal models will help us learn how to reduce PEM not only for patients with ME/CFS, but also for patients with other diseases and processes in which dysregulated autophagy drives chronic inflammation or muscle fatigue (e.g., aging, Alzheimer’s disease, cancer, and Parkinson’s).

Dr. Roy has had fantastic success since winning his Ramsay award. In addition to publishing these studies and launching these trials, he also published research on other key symptoms of ME/CFS and on another chemical that improves functioning of neurons derived from patients with Alzheimer’s disease. That paper (JRM-28, a Novel HDAC2 Inhibitor, Upregulates Plasticity-Associated Proteins in Hippocampal Neurons and Enhances Morphological Plasticity via Activation of CREB: Implications for Alzheimer’s Disease) appears in the journal Cells and thanks Solve for support.

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