Naddaf, E. | bioRxiv Science

bioRxiv2026

Multilevel impairment of mitochondrial respiration with sex-specific signatures in inclusion body myositis

BackgroundOxidative phosphorylation (OXPHOS) is a central function and a key indicator of mitochondrial fitness, yet studies in human tissue remain limited. Inclusion body myositis (IBM) is a progressive myopathy that lies at the intersection of aging, inflammation and mitochondrial dysfunction. We aimed to perform a comprehensive profiling of mitochondrial respiration in muscle tissue from patients with IBM. MethodsA wide battery of complementary tests from RNA level to high-resolution respirometry on permeabilized muscle fibers was performed. The relationship between respiration, mitochondrial content, mitochondrial DNA (mtDNA) abnormalities and mitophagy was examined, along with the correlation with various clinical parameters to determine the clinical significance of the findings. ResultsThe study included a total of 67 patients with IBM and 45 controls. IBM muscle tissue exhibited reduced maximal respiration per tissue weight in State 3 (high substrates, high ADP) and uncoupled state with decreased coupling efficiency and higher leak control ratios. When adjusting for citrate synthase reflecting mitochondrial content, males had decreased State 3 intrinsic respiration, whereas females had greater intrinsic respiration in leak states. Complex II control ratio strongly correlated with disease duration and severity only in females. IBM was associated with decreased RNA and protein expression of OXPHOS complexes. Complex I activity was decreased mainly in females. IBM samples exhibited lower maximal H2O2 emission, accompanied by a higher total antioxidant capacity that correlated with disease duration in females. In IBM, there was decreased mtDNA content, and impaired mitophagy, both of which strongly correlated with respirometry measures and markers of disease severity, indicating these pathways are likely interconnected and of clinical significance. ConclusionIBM is characterized by multilevel impairments in mitochondrial coupling efficiency, revealing several potential therapeutic targets to improve mitochondrial fitness, while accounting for sex-specific differences.

neuroscience↗

bioRxiv2024

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

BackgroundInclusion 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. ObjectiveTo 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. Methods37 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 metabolomics, Agilent dMRM Database and Method platform, and targeted metabolomics. Metabolite levels and RNA-metabolomics integrated modules were correlated with clinical parameters. ResultsMuscle 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. ConclusionTaken 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 determine the role of the detected metabolic alterations in IBM pathogenesis and track the changes longitudinally over the disease course.

neuroscience↗