Skeletal Muscle mRNA Splicing Variants Association With Four Different Fitness and Energetic Measures in the GESTALT Study
ABSTRACT Background Physical activity is essential for maintaining muscle mitochondrial function and aerobic capacity. The molecular mechanisms underlying such protective effects are incompletely understood, in part because it is difficult to separate the effects of disease status and physical activ...
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Wiley
2025-02-01
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| Series: | Journal of Cachexia, Sarcopenia and Muscle |
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| Online Access: | https://doi.org/10.1002/jcsm.13603 |
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| author | Stefano Donega Nirad Banskota Esha Gupta Marta Gonzalez‐Freire Ann Zenobia Moore Ceereena Ubaida‐Mohien Rachel Munk Linda Zukley Yulan Piao Chris Bergeron Jan Bergeron Arsun Bektas Marta Zampino Carole Stagg Fred Indig Lisa M. Hartnell Mary Kaileh Kenneth Fishbein Richard G. Spencer Myriam Gorospe Supriyo De Josephine M. Egan Ranjan Sen Luigi Ferrucci |
| author_facet | Stefano Donega Nirad Banskota Esha Gupta Marta Gonzalez‐Freire Ann Zenobia Moore Ceereena Ubaida‐Mohien Rachel Munk Linda Zukley Yulan Piao Chris Bergeron Jan Bergeron Arsun Bektas Marta Zampino Carole Stagg Fred Indig Lisa M. Hartnell Mary Kaileh Kenneth Fishbein Richard G. Spencer Myriam Gorospe Supriyo De Josephine M. Egan Ranjan Sen Luigi Ferrucci |
| author_sort | Stefano Donega |
| collection | DOAJ |
| description | ABSTRACT Background Physical activity is essential for maintaining muscle mitochondrial function and aerobic capacity. The molecular mechanisms underlying such protective effects are incompletely understood, in part because it is difficult to separate the effects of disease status and physical activity. We explored the association of human skeletal muscle transcriptomic with four measures of energetics and mitochondria oxidative capacity in healthy individuals. Methods Using RNA sequencing of vastus lateralis muscle biopsies from 82 GESTALT participants (52 males, aged 22–89 years), we explored gene and splicing variant expression profiles associated with self‐reported physical activity, peak oxygen consumption (VO2 peak), muscle oxidative capacity (kPCr) and mitochondrial respiration (Mit‐O2 flux). The effect of aging on gene expression was examined in participants with low and high VO2 peak. Results The four measures of energetics were negative correlated with age and generally intercorrelated. We identified protein‐coding genes associated with four energetic measures adjusting for age, muscle fiber‐ratio, sex and batch effect. Mitochondrial pathways were overrepresented across all energetic variables, albeit with little overlap at the gene level. Alternative spliced transcript isoforms associated with energetics were primarily enriched for cytoplasmic ribonucleoprotein granules. The splicing pathway was up‐regulated with aging in low but not in high fitness participants, and transcript isoforms detected in the low fitness group pertain to processes such as cell cycle regulation, RNA/protein localization, nuclear transport and catabolism. Conclusions A consistent mitochondrial signature emerged across all energetic measures. Alternative splicing was enhanced in older, low fitness participants supporting the energy‐splicing axis hypothesis. The identified splicing variants were enriched in pathways involving the accumulation of ribonucleoproteins in cytoplasmic granules, whose function remains unclear. Further research is needed to understand the function of these proteoforms in promoting adaptation to low energy availability. |
| format | Article |
| id | doaj-art-ec7e1389499d44299bc5a6a441ad3ff7 |
| institution | OA Journals |
| issn | 2190-5991 2190-6009 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Cachexia, Sarcopenia and Muscle |
| spelling | doaj-art-ec7e1389499d44299bc5a6a441ad3ff72025-08-20T02:06:27ZengWileyJournal of Cachexia, Sarcopenia and Muscle2190-59912190-60092025-02-01161n/an/a10.1002/jcsm.13603Skeletal Muscle mRNA Splicing Variants Association With Four Different Fitness and Energetic Measures in the GESTALT StudyStefano Donega0Nirad Banskota1Esha Gupta2Marta Gonzalez‐Freire3Ann Zenobia Moore4Ceereena Ubaida‐Mohien5Rachel Munk6Linda Zukley7Yulan Piao8Chris Bergeron9Jan Bergeron10Arsun Bektas11Marta Zampino12Carole Stagg13Fred Indig14Lisa M. Hartnell15Mary Kaileh16Kenneth Fishbein17Richard G. Spencer18Myriam Gorospe19Supriyo De20Josephine M. Egan21Ranjan Sen22Luigi Ferrucci23Longitudinal Studies Section (LSS) National Institute on Aging (NIA), National Institutes of Health (NIH) Baltimore Maryland USALaboratory of Genetics and Genomics (LGG) National Institute on Aging (NIA), National Institutes of Health (NIH) Baltimore Maryland USALaboratory of Genetics and Genomics (LGG) National Institute on Aging (NIA), National Institutes of Health (NIH) Baltimore Maryland USATranslational Research in Aging and Longevity Group (TRIAL group) Fundació Institut d'Investigació Sanitària Illes Balears (IdISBa) Palma de Mallorca SpainLongitudinal Studies Section (LSS) National Institute on Aging (NIA), National Institutes of Health (NIH) Baltimore Maryland USALongitudinal Studies Section (LSS) National Institute on Aging (NIA), National Institutes of Health (NIH) Baltimore Maryland USALaboratory of Genetics and Genomics (LGG) National Institute on Aging (NIA), National Institutes of Health (NIH) Baltimore Maryland USAClinical Research Core (CRC) National Institute on Aging (NIA), National Institutes of Health (NIH) Baltimore Maryland USALaboratory of Genetics and Genomics (LGG) National Institute on Aging (NIA), National Institutes of Health (NIH) Baltimore Maryland USAClinical Research Core (CRC) National Institute on Aging (NIA), National Institutes of Health (NIH) Baltimore Maryland USAClinical Research Core (CRC) National Institute on Aging (NIA), National Institutes of Health (NIH) Baltimore Maryland USAClinical Research Core (CRC) National Institute on Aging (NIA), National Institutes of Health (NIH) Baltimore Maryland USALongitudinal Studies Section (LSS) National Institute on Aging (NIA), National Institutes of Health (NIH) Baltimore Maryland USAConfocal Imaging Facility National Institute on Aging (NIA), National Institutes of Health (NIH) Baltimore Maryland USAConfocal Imaging Facility National Institute on Aging (NIA), National Institutes of Health (NIH) Baltimore Maryland USALongitudinal Studies Section (LSS) National Institute on Aging (NIA), National Institutes of Health (NIH) Baltimore Maryland USAClinical Research Core (CRC) National Institute on Aging (NIA), National Institutes of Health (NIH) Baltimore Maryland USAClinical Research Core (CRC) National Institute on Aging (NIA), National Institutes of Health (NIH) Baltimore Maryland USALaboratory of Clinical Investigation National Institute on Aging (NIA), National Institutes of Health (NIH) Baltimore Maryland USALaboratory of Genetics and Genomics (LGG) National Institute on Aging (NIA), National Institutes of Health (NIH) Baltimore Maryland USALaboratory of Genetics and Genomics (LGG) National Institute on Aging (NIA), National Institutes of Health (NIH) Baltimore Maryland USAClinical Research Core (CRC) National Institute on Aging (NIA), National Institutes of Health (NIH) Baltimore Maryland USALaboratory of Molecular Biology and Immunology (LMBI) National Institute on Aging (NIA), National Institutes of Health (NIH) Baltimore Maryland USALongitudinal Studies Section (LSS) National Institute on Aging (NIA), National Institutes of Health (NIH) Baltimore Maryland USAABSTRACT Background Physical activity is essential for maintaining muscle mitochondrial function and aerobic capacity. The molecular mechanisms underlying such protective effects are incompletely understood, in part because it is difficult to separate the effects of disease status and physical activity. We explored the association of human skeletal muscle transcriptomic with four measures of energetics and mitochondria oxidative capacity in healthy individuals. Methods Using RNA sequencing of vastus lateralis muscle biopsies from 82 GESTALT participants (52 males, aged 22–89 years), we explored gene and splicing variant expression profiles associated with self‐reported physical activity, peak oxygen consumption (VO2 peak), muscle oxidative capacity (kPCr) and mitochondrial respiration (Mit‐O2 flux). The effect of aging on gene expression was examined in participants with low and high VO2 peak. Results The four measures of energetics were negative correlated with age and generally intercorrelated. We identified protein‐coding genes associated with four energetic measures adjusting for age, muscle fiber‐ratio, sex and batch effect. Mitochondrial pathways were overrepresented across all energetic variables, albeit with little overlap at the gene level. Alternative spliced transcript isoforms associated with energetics were primarily enriched for cytoplasmic ribonucleoprotein granules. The splicing pathway was up‐regulated with aging in low but not in high fitness participants, and transcript isoforms detected in the low fitness group pertain to processes such as cell cycle regulation, RNA/protein localization, nuclear transport and catabolism. Conclusions A consistent mitochondrial signature emerged across all energetic measures. Alternative splicing was enhanced in older, low fitness participants supporting the energy‐splicing axis hypothesis. The identified splicing variants were enriched in pathways involving the accumulation of ribonucleoproteins in cytoplasmic granules, whose function remains unclear. Further research is needed to understand the function of these proteoforms in promoting adaptation to low energy availability.https://doi.org/10.1002/jcsm.13603agingalternative splicingenergyexercisekPCrmitochondria respirometry |
| spellingShingle | Stefano Donega Nirad Banskota Esha Gupta Marta Gonzalez‐Freire Ann Zenobia Moore Ceereena Ubaida‐Mohien Rachel Munk Linda Zukley Yulan Piao Chris Bergeron Jan Bergeron Arsun Bektas Marta Zampino Carole Stagg Fred Indig Lisa M. Hartnell Mary Kaileh Kenneth Fishbein Richard G. Spencer Myriam Gorospe Supriyo De Josephine M. Egan Ranjan Sen Luigi Ferrucci Skeletal Muscle mRNA Splicing Variants Association With Four Different Fitness and Energetic Measures in the GESTALT Study Journal of Cachexia, Sarcopenia and Muscle aging alternative splicing energy exercise kPCr mitochondria respirometry |
| title | Skeletal Muscle mRNA Splicing Variants Association With Four Different Fitness and Energetic Measures in the GESTALT Study |
| title_full | Skeletal Muscle mRNA Splicing Variants Association With Four Different Fitness and Energetic Measures in the GESTALT Study |
| title_fullStr | Skeletal Muscle mRNA Splicing Variants Association With Four Different Fitness and Energetic Measures in the GESTALT Study |
| title_full_unstemmed | Skeletal Muscle mRNA Splicing Variants Association With Four Different Fitness and Energetic Measures in the GESTALT Study |
| title_short | Skeletal Muscle mRNA Splicing Variants Association With Four Different Fitness and Energetic Measures in the GESTALT Study |
| title_sort | skeletal muscle mrna splicing variants association with four different fitness and energetic measures in the gestalt study |
| topic | aging alternative splicing energy exercise kPCr mitochondria respirometry |
| url | https://doi.org/10.1002/jcsm.13603 |
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