ArticleJournal of cachexia, sarcopenia and muscle2025
NLRP3 Inflammasome Activation and Altered Mitophagy Are Key Pathways in Inclusion Body Myositis.
Article in Journal of cachexia, sarcopenia and muscle, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed.
- Mitophagy in cisplatin-induced kidney injury: regulatory mechanisms and therapeutic targets.Annals of medicine · 2026Review
- Metainflammation, Mitochondrial Dysfunction, and Organokine Crosstalk: A Central Axis Linking Metabolic Syndrome to Cardiovascular Diseases.International journal of molecular sciences · 2026Review
- Targeting Mitochondria in Aging-Related Diseases: Therapeutic Potential and Obstacles.MedComm · 2026Review
- High-plex spatial protein profiling of skeletal muscle biopsies in inflammatory myopathies using the MACSima™ imaging platform: A pilot study.Acta neuropathologica communications · 2026Article
- Review
- Multilevel impairment of mitochondrial respiration with sex-specific signatures in inclusion body myositis.bioRxiv : the preprint server for biology · 2026Article
- Mitochondria-centred metabolomic map of inclusion body myositis: sex-specific alterations in central carbon metabolism.Annals of the rheumatic diseases · 2025Article
- Increased Risk of Myocardial Infarction in Inclusion Body Myositis: A Non-Concurrent Cohort Study.European journal of neurology · 2025Article
- Inflammasomes and idiopathic inflammatory myopathies.Frontiers in immunology · 2024Review
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12 authors.
Funding
Abstract
backgroundInclusion body myositis (IBM) is the most prevalent muscle disease in adults for which no current treatment exists. The pathogenesis of IBM remains poorly defined. In this study, we aimed to explore the interplay between inflammation and mitochondrial dysfunction in IBM.
methodsThe study population consisted of 38 IBM patients and 22 age- and sex-matched controls without a myopathy. Mean age was 62.9 years (SD = 9) in IBM group and 59.7 (10) in controls. Bulk RNA sequencing, Meso Scale Discovery electrochemiluminescence (ECL), western blotting, histochemistry and immunohistochemistry were performed on frozen muscle samples from the study participants.
resultsWe demonstrated activation of the NLRP3 inflammasome in IBM muscle samples, with the NLRP3 inflammasome being the most upregulated pathway on RNA sequencing, along with increased expression of NLRP3 and ASC proteins in IBM group. NLRP3 RNA levels most strongly correlated with TLR7 (correlation coefficient ρ = 0.91) and complement activation-related genes, and inversely correlated with several mitochondria-related genes among others. On muscle histopathology, there was increased NRLP3 immunoreactivity in both inflammatory cells and muscle fibres. Mitophagy is critical for removing damaged mitochondria and preventing the formation of a vicious cycle of mitochondrial dysfunction-NLRP3 inflammasome activation. Herein, we showed altered mitophagy, as witnessed by the elevated levels of p-S65-Ubiquitin, a mitophagy marker, in muscle lysates from IBM patients compared to controls (median of 114.3 vs. 81.25 ECL units, p = 0.005). The p-S65-Ubiquitin levels were most significantly elevated in IBM males compared to male controls (136 vs. 83.5 ECL units; p = 0.013), whereas IBM females had milder nonsignificant elevation compared to female controls (97.25 vs. 69 ECL units, p = 0.31). On muscle histopathology, p-S65-Ubiquitin aggregates accumulated in muscle fibres that were mostly Type 2 and devoid of cytochrome-c-oxidase reactivity. NLRP3 RNA levels correlated with p-S65-Ubiquitin levels in both sexes (males: ρ = 0.48, females: ρ = 0.54) but with loss of muscle strength, as reflected by the manual motor test score, only in males (males: ρ = 0.62, females: ρ = -0.14). Lastly, we identified sex-specific molecular pathways in IBM. Females had upregulation of pathways related to response to stress, which could conceivably offset some of the pathomechanisms of IBM, while males had upregulation of pathways related to cell adhesion and migration.
conclusionsThere is activation of the NLRP3 inflammasome in IBM, along with altered mitophagy, particularly in males, which is of potential therapeutic significance. These findings suggest sex-specific mechanisms in IBM that warrant further investigation.
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