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NIH grant 1RF1NS146397-01A1: The Central Role of mTOR in ME/CFS Pathogenesis.
Institute: {'code': 'NS', 'abbreviation': 'NINDS', 'name': 'National Institute of Neurological Disorders and Stroke', 'admin_org_id': '12500053', 'admin_funding_url': ''}. PI: C. GUNNAR Gottschalk. Award: $780000.
Start: 2026-09-25T00:00:00.
PROJECT SUMMARY. Myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) is a multisystem
chronic illness characterized by severe muscle fatigue, pain, dizziness, and brain fog. Many patients with
ME/CFS experience Post-exertional malaise (PEM), which is characterized by severe muscle fatigue, pain, and
cognitive impairment after physical or mental exercise. Despite intense investigation, the molecular mechanism
of this debilitating condition is still unknown. Recently, we reported that the chronic activation of mammalian
target of rapamycin (mTOR) may play a critical role in the pathogenesis of PEM. First, the chronic administration
of selective mTOR agonist MHY1485 was observed to induce severe spontaneous and post-exertional muscle
fatigue after a single session-treadmill exercise. Second, histopathological analyses of skeletal muscle revealed
that there was a strong infiltration of mononuclear cells in the vasculature of muscle tissue upon chronic induction
of the mTOR activation. Further analysis revealed that these mononuclear cells are macrophages strongly
expressed inflammatory surface marker CD40 and enzyme iNOS suggesting the potential role of mTOR
activation in the infiltration and polarization of Mφ to its inflammatory mode (M1Mφ) . Third, we observed that the
activation of mTOR directly inhibited the autophagy process via suppressing the activity of early autophagy
protein ATG13 in these mice. Autophagy is a quality control process for mitochondrial health and function.
Accordingly, the genetic mutation of the early autophagy gene atg13 followed by the autophagy impairment
stimulated severe spontaneous and post-exertional muscle fatigue. The subsequent molecular analyses also
revealed that the genetic ablation of atg13 caused severe infiltration of inflammatory macrophages in the
vasculature of skeletal muscle. Finally, we observed that the chronic activation of mTOR induced the activation
of a nuclear transcription factor named STAT3 causing the secretion of inflammatory mediators such as IL6 and
RANTES. Therefore, we hypothesize that the activation of mTOR plays a central role in the pathogenesis of
PEM. The central objective will be studied in three specific aims. In aim1, we will study the effect of mTOR
activation on the polarization of M1Mφ in PEM pathogenesis. Here we applied a novel oxygen-deficient cell
culture model, in which Mφ cells will be treated with plasma samples of ME/CFS patients and ME/CFS patients
treated with 6mg/Kg/week rapamycin for 30 days (T1). In aim 2, we will study the molecular mechanism on how
the mTOR activation polarizes M1 phenotype. The role of mTOR on ATG13 inactivation will be evaluated in a
novel atg13∆muscle strain, in which atg13 gene is selectively knocked out in muscle. We also developed a new
ELISA kit to study mTOR mediated Serine 258 phosphorylation of ATG13. Our proposed research will further
investigate how the mTOR-mediated activation of STAT3 employs the polarization of M1Mφ cells. Under aim3,
we propose a comprehensive metabolomic study to investigate the role of mTOR activation in regulating the
purine and glucose metabolism in ME/CFS cases, which potentially regulates the polarization of M1Mφ cells.document fetched 2026-10-04 02:43