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

Abstract

Background: Inclusion body myositis (IBM) is a disease of aging characterized by progressive muscle loss. Despite its positioning at the intersection of aging, mitochondrial dysfunction and chronic inflammation, limited studies have evaluated the underlying metabolic disturbances in IBM. Objective: To investigate the mitochondria-centered metabolomic map of IBM in muscle tissue, highlighting sex-specific differences, and to determine the correlation of the changes in metabolites and gene expression with clinical parameters. Methods: 37 IBM patients and 22 controls without a myopathy were included. All participants had bulk RNA sequencing performed previously. Clinical parameters included age at biopsy, disease duration, manual motor test (MMT) score, and modified Rankin scale (MRS). A complementary battery of metabolomics platforms was used including untargeted, targeted, and central carbon metabolism. Metabolite levels and RNA-metabolomics integrated modules were correlated with clinical parameters. Results: Muscle samples from IBM patients had elevated TCA cycle intermediates with concomitant increase in anaplerotic amino acids, suggesting increased anaplerosis into the cycle. There was a decrease in upper glycolysis intermediates and an increase in most of the pentose phosphate pathway (PPP) metabolites. The PPP is the main source of NAPDH, a main antioxidant, and ribose-5-P a precursor of nucleic acids. There were marked sex-specific differences in the acylcarnitine profile, with a decrease in short-chain acylcarnitines only in males. Lastly, there was an increase in nucleic acid bases and a decrease in nucleotides. Several metabolites from various pathways had significant correlations with various clinical parameters, with the most pronounced sex-specific differences observed in correlations with acylcarnitines. RNA-metabolomics integration identified 4 modules, with the strongest correlation observed between one module and sex. The MMT score, an indicator of disease severity, showed a strong correlation with 3 modules. There were major sex specific differences with males having relatively similar correlation to the grouped (both sexes) analysis, while females had no significant correlation with any of the modules. Conclusion: Taken together, our findings identified clinically significant alterations in central carbon metabolism in IBM, with major differences between males and females. Future studies are needed to detect the longitudinal changes in metabolites over the disease course.