Mitochondria-centred metabolomic map of inclusion body myositis: sex-specific alterations in central carbon metabolism.

Objectives: To benchmark metabolomic signatures of inclusion body myositis (IBM) in muscle tissue, highlighting sex-specific differences and the correlation with clinical parameters.

Methods: A total of 37 IBM patients and 22 controls without myopathy were included. All participants had bulk RNA sequencing performed previously. Clinical parameters included disease duration and manual muscle test (MMT) scores. Discovery metabolite screening and quantitative targeted metabolomics platforms were used. Levels of metabolites and RNA-metabolomic integrated modules were correlated with clinical parameters and the mitophagy marker, p-S65-Ubiquitin (p-S65-Ub).

Results: IBM muscle samples showed elevated citric acid (TCA) cycle intermediates and anaplerotic amino acids. Proximal glycolytic intermediates were decreased, while pentose phosphate pathway (PPP) metabolites were increased. Short-chain acylcarnitines were lower in IBM males but not in females. Lastly, nucleic acid bases were increased, and nucleotides were decreased. MMT correlated with PPP metabolites and nucleic acid bases, and inversely correlated with glycolysis metabolites and mono/diphosphate nucleotides. MMT also correlated with several amino acids, including cysteine, taurine, carnosine, and sarcosine. Acylcarnitines correlated with disease duration only in males. Four RNA-metabolomic integrated modules demonstrated significant correlations. The strongest correlations were observed between the pink module and both sexes and p-S65-Ub. MMT and p-S65-Ub correlated with 3 and 2 modules, respectively. The enriched pathways were related to central carbon metabolism, cytokine/chemokine signalling, neurotransmission, and mitogen-activated protein kinase (MAPK)/RAS signalling. Males had relatively similar correlations to the combined-sex analysis, while females had no significant correlation with any module.

Conclusions: IBM is associated with clinically significant alterations in central carbon metabolism, with the strongest RNA-metabolomic-clinical correlations observed in males. Further research is needed to explore the role of these metabolic changes in IBM pathogenesis and their progression over time.