Biology subjects

Lanza, I. R.

Publications and source records attributed to Lanza, I. R..

2 recordsLinked to original sources

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↗

bioRxiv2022

Temporal dynamics of the multi-omic response to endurance exercise training across tissues

Regular exercise promotes whole-body health and prevents disease, yet the underlying molecular mechanisms throughout a whole organism are incompletely understood. Here, the Molecular Transducers of Physical Activity Consortium (MoTrPAC) profiled the temporal transcriptome, proteome, metabolome, lipidome, phosphoproteome, acetylproteome, ubiquitylproteome, epigenome, and immunome in whole blood, plasma, and 18 solid tissues in Rattus norvegicus over 8 weeks of endurance exercise training. The resulting data compendium encompasses 9466 assays across 19 tissues, 25 molecular platforms, and 4 training time points in young adult male and female rats. We identified thousands of shared and tissue- and sex-specific molecular alterations. Temporal multi-omic and multi-tissue analyses demonstrated distinct patterns of tissue remodeling, with widespread regulation of immune, metabolism, heat shock stress response, and mitochondrial pathways. These patterns provide biological insights into the adaptive responses to endurance training over time. For example, exercise training induced heart remodeling via altered activity of the Mef2 family of transcription factors and tyrosine kinases. Translational analyses revealed changes that are consistent with human endurance training data and negatively correlated with disease, including increased phospholipids and decreased triacylglycerols in the liver. Sex differences in training adaptation were widespread, including those in the brain, adrenal gland, lung, and adipose tissue. Integrative analyses generated novel hypotheses of disease relevance, including candidate mechanisms that link training adaptation to non-alcoholic fatty liver disease, inflammatory bowel disease, cardiovascular health, and tissue injury and recovery. The data and analysis results presented in this study will serve as valuable resources for the broader community and are provided in an easily accessible public repository (https://motrpac-data.org/). HighlightsO_LIMulti-tissue resource identifies 35,439 analytes regulated by endurance exercise training at 5% FDR across 211 combinations of tissues and molecular platforms. C_LIO_LIInterpretation of systemic and tissue-specific molecular adaptations produced hypotheses to help describe the health benefits induced by exercise. C_LIO_LIRobust sex-specific responses to endurance exercise training are observed across multiple organs at the molecular level. C_LIO_LIDeep multi-omic profiling of six tissues defines regulatory signals for tissue adaptation to endurance exercise training. C_LIO_LIAll data are available in a public repository, and processed data, analysis results, and code to reproduce major analyses are additionally available in convenient R packages. C_LI

molecular biology↗