Irisin Signaling Resistance in ME: A Proposed Mechanistic Framework for Post-Exertional Malaise Involving the TSP-1–HSP90α–αvβ5, 2026, Moreau et al

[John Mac]

Full title: Irisin Signaling Resistance in Myalgic Encephalomyelitis: A Proposed Mechanistic Framework for Post-Exertional Malaise Involving the TSP-1–HSP90α–αvβ5 Axis

Abstract​

Myalgic Encephalomyelitis (ME) is a chronic, multisystem disease characterized by systemic metabolic dysfunction and post-exertional malaise (PEM).

In this study, we investigated the dysregulation of irisin, an exercise-induced myokine, and its potential antagonism by thrombospondin-1 (TSP-1).

In a cross-sectional study (92 ME patients vs. 44 sedentary healthy controls), plasma irisin and TSP-1 levels were measured at baseline and after a 90 min mechanical stress challenge applied to induce PEM.

ME patients exhibited significantly lower baseline irisin (p < 0.05) and a blunted exertional response (p < 0.05).

Paradoxically, baseline irisin was an independent predictor of fatigue severity (β = 0.728, p = 0.018), with moderate-to-severe patients showing elevated levels of both irisin and TSP-1 (p < 0.05), suggesting a compensatory but ineffective response.

Functional cellular dielectric spectroscopy indicated that TSP-1 inhibits irisin signaling in a concentration-dependent manner.

Irisin signaling was markedly reduced by both αvβ5 blockade and HSP90α inhibition in this experimental system, consistent with a diminished ability to counteract TSP-1.

Collectively, these findings support a model in which dysregulation of the irisin–TSP-1 axis contributes to metabolic dysfunction in ME.

Elevated circulating TSP-1 levels are associated with symptom severity and are linked to impaired irisin signaling in an HSP90α- and αvβ5-dependent context.

This interaction is consistent with defective metabolic adaptation and highlights a potential therapeutic target that warrants further validation to restore energy homeostasis.

https://www.mdpi.com/1422-0067/27/11/4770

 

[wallfish]

I found it interesting that participants didn't do any actual exercise. Exercise was simulated.

To evaluate the dynamic physiological response to exertion, a subset of the recruited cohort underwent a standardized 90 min mechanical stimulation protocol designed to mimic the physiological stress of physical activity [1]. [...] This standardized protocol involved applying intermittent pneumatic compression to the upper arm with a device calibrated to deliver cyclic pressure variations (frequency: 0.006 Hz; pressure range: 0–4 psi). This specific frequency and pressure were selected to stimulate hemodynamic and vascular responses that partially recapitulate the physiological effects of physical exertion. Importantly, this model was designed to reproduce key circulatory and mechanotransductive components of exercise while minimizing confounding factors such as systemic metabolic exhaustion, excessive cardiovascular strain, and variability in physical performance. This approach is particularly relevant in ME populations, where conventional exercise testing may exacerbate symptoms and introduce significant inter-individual variability. Moreover, the use of a low-burden, non-exertional stimulation paradigm facilitates participation of patients with higher symptom severity who may otherwise be underrepresented in exercise-based studies.

This was new to me, but it has been discussed before on this forum in the thread for their reference [1].