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RNA Sequencing on Muscle Biopsies from Exertional Rhabdomyolysis Patients Revealed Down-Regulation of Mitochondrial Function and Enhancement of Extracellular Matrix Composition.
Abstract: Exertional rhabdomyolysis (ER) is primarily driven by mechanical stress on muscles during strenuous or unaccustomed exercise, often exacerbated by environmental factors like heat and dehydration. While the general cellular pathway involving energy depletion and calcium overload is understood in horse ER models, the underlying mechanisms specific to the ER are not universally known within humans. This study aimed to evaluate whether patients with ER exhibited transcriptional signatures that were significantly different from those of healthy individuals. Methods: This study utilized RNA sequencing on skeletal muscle samples from 19 human patients with ER history, collected at a minimum of six months after the most recent ER event, and eight healthy controls to investigate the transcriptomic landscape of ER. To identify any alterations in biological processes between the case and control groups, functional pathway analyses were conducted. Results: Functional pathway enrichment analyses of differentially expressed genes revealed strong suppression of mitochondrial function. This suppression included the "aerobic electron transport chain" and "oxidative phosphorylation" pathways, indicating impaired energy production. Conversely, there was an upregulation of genes associated with adhesion and extracellular matrix-related pathways, indicating active restoration of muscle function in ER cases. Conclusions: The study demonstrated that muscle tissue exhibited signs of suppressed mitochondrial function and increased extracellular matrix development. Both of these facilitate muscle recovery within several months after an ER episode.
Publication Date: 2025-08-02 PubMed ID: 40869978PubMed Central: PMC12386086DOI: 10.3390/genes16080930Google Scholar: Lookup The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
- Journal Article
Summary
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RNA sequencing of muscle biopsies from patients who experienced exertional rhabdomyolysis revealed reduced mitochondrial function and increased activity related to the extracellular matrix, suggesting ongoing muscle recovery months after the injury.
Background and Purpose
- Exertional rhabdomyolysis (ER) is muscle damage caused by severe or unusual physical exercise, often worsened by factors like heat and dehydration.
- In animal models, ER mechanisms involve energy depletion and calcium overload in muscle cells, but these mechanisms are less well understood in humans.
- The study’s goal was to investigate whether muscle tissue from ER patients shows different gene expression patterns compared to healthy individuals, to better understand the biological changes involved in this condition.
Methods
- Researchers collected skeletal muscle biopsy samples from two groups: 19 patients with a history of ER (at least six months after their last ER event) and 8 healthy control participants.
- RNA sequencing was performed on these muscle samples to analyze gene expression profiles.
- Differential gene expression analysis was then used to identify significant changes between ER patients and controls.
- Functional pathway enrichment analysis was conducted to determine which biological processes were affected by these gene expression changes.
Key Findings
- ER patients exhibited significant down-regulation of genes related to mitochondrial functions:
- Specifically, genes involved in the “aerobic electron transport chain” and “oxidative phosphorylation” pathways were suppressed.
- This indicates that energy production in muscle mitochondria is impaired after ER events.
- Conversely, an upregulation of genes associated with adhesion and extracellular matrix (ECM) pathways was observed:
- This suggests increased synthesis and remodeling of ECM components.
- Such ECM changes likely support muscle repair and structural recovery following injury.
- These gene expression patterns reflect ongoing biological processes several months post-ER, implying a persisting state of muscle recovery rather than acute damage.
Conclusions and Implications
- The study provides evidence that muscle tissues from ER patients show a dual response after injury: suppressed mitochondrial energy metabolism and enhanced extracellular matrix production.
- This molecular signature likely represents the muscle’s adaptation and repair processes occurring during the recovery phase following ER episodes.
- Understanding these transcriptomic changes can help guide future research on therapeutic interventions and monitoring muscle recovery in ER patients.
- The results also underscore the importance of mitochondrial function and extracellular matrix remodeling in muscle health and rehabilitation after exertional injury.
Cite This Article
APA
Ren M, Michaelson LP, Mungunsukh O, Bedocs P, Friel L, Cofer K, Dartt CE, Sambuughin N, O'Connor FG.
(2025).
RNA Sequencing on Muscle Biopsies from Exertional Rhabdomyolysis Patients Revealed Down-Regulation of Mitochondrial Function and Enhancement of Extracellular Matrix Composition.
Genes (Basel), 16(8), 930.
https://doi.org/10.3390/genes16080930 Publication
Researcher Affiliations
- Consortium for Health and Military Performance, Department of Military and Emergency Medicine, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
- Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA.
- Department of Anesthesiology, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
- Department of Veterans Affairs, Baltimore VA Medical Healthcare System, Baltimore, MD 21201, USA.
- Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA.
- Department of Anatomy, Physiology and Genetics, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
- Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA.
- Department of Anesthesiology, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
- Defense & Veterans Center for Integrative Pain Management, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
- Consortium for Health and Military Performance, Department of Military and Emergency Medicine, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
- Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA.
- Consortium for Health and Military Performance, Department of Military and Emergency Medicine, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
- Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA.
- Consortium for Health and Military Performance, Department of Military and Emergency Medicine, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
- Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA.
- Consortium for Health and Military Performance, Department of Military and Emergency Medicine, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
- Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA.
- Consortium for Health and Military Performance, Department of Military and Emergency Medicine, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
MeSH Terms
- Humans
- Rhabdomyolysis / genetics
- Rhabdomyolysis / pathology
- Rhabdomyolysis / metabolism
- Male
- Adult
- Muscle, Skeletal / metabolism
- Muscle, Skeletal / pathology
- Mitochondria / genetics
- Mitochondria / metabolism
- Female
- Extracellular Matrix / metabolism
- Extracellular Matrix / genetics
- Down-Regulation
- Sequence Analysis, RNA
- Biopsy
- Transcriptome
- Middle Aged
Grant Funding
- PPG-ANE-80-3397 / USU Intramural Research
- HU0001-14-1-0060 / NHLBI NIH HHS
Conflict of Interest Statement
The opinions and assertions expressed herein are those of the authors and do not necessarily reflect the official policy or position of the Uniformed Services University or the Department of Defense. The contents of this publication are the sole responsibility of the authors and do not necessarily reflect the views, opinions, or policies of the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. Mention of trade names, commercial products, or organizations does not imply endorsement by the US Government.
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