Integrated Single-Myofibre Multi-Omics Correlates Inflammatory State to Myosin Energetics in ICU-Acquired Weakness.
8 affiliations
- 1Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
- 2Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
- 3Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, Università di Brescia, Brescia, Italy.
- 4Amsterdam UMC, Location VUmc, Department of Physiology, Amsterdam, the Netherlands.
- 5Department of Cellular and Molecular Medicine, University of Arizona, Tucson, Arizona, USA.
- 6ASST Spedali Civili di Brescia, ASST Spedali Civili, Dept. of Bone and Joint Surgery, Brescia, Italy.
- 7Department of Anesthesia, Critical Care and Emergency, ASST Spedali Civili University Hospital, Brescia, Italy.
- 8Centre of Human and Applied Physiological Sciences, School of Basic and Medical Biosciences, Faculty of Life Sciences & Medicine, King's College London, London, UK.
Abstract
Background
Skeletal muscle atrophy is a pervasive complication of critical illness that worsens survival and recovery, yet remains poorly explained by current clinical or molecular markers.Methods
To directly connect disease-associated molecular states to the contractile machinery, this study combined sequential functional, transcriptomic and proteomic profiling of the same single human skeletal myofibres from critically ill patients in the intensive care unit with acquired weakness (ICU-AW) and controls. This integrated approach provides a framework for validating molecular signals directly within the cellular and biomechanical context.Results
Differential expression analyses between control and ICU-AW myofibres show marked donor-level heterogeneity, with no differentially expressed features (FDR < 0.05). Ranked gene set enrichment analyses revealed distinct transcriptional and proteomic signatures between conditions, as well as a subtle yet conserved myofibre state enriched in ICU-AW, characterised by inflammatory and chemotactic gene programmes, intracellular structural remodelling and bioenergetic adaptation. Nineteen features were significantly (FDR < 0.05) altered at both RNA and protein levels from the same myofibre. Overall, these 19 overlapping features link an inflammatory transcriptional landscape to a proteomic shift toward mitochondrial and translational machinery, revealing a coordinated stress-adaptation programme with selective post-translational control in fibres from patients with ICU-AW. Further integration with the functional dataset revealed fibres in this state displayed selectively disrupted myosin dynamics, evidenced by prolonged ATP turnover time of myosin heads in their super-relaxed conformation, suggesting altered myosin energetics as a contributor to muscle dysfunction.Conclusions
These findings define a discrete, disease-associated myofibre state and validate a proof-of-concept integrative single-fibre framework for connecting multi-omic heterogeneity to molecular motor function in complex human disease. The identification of coordinated transcriptomic and proteomic programmes, validated through functional measurement, suggests that targeting this fibre state may offer new therapeutic opportunities in ICU-acquired dysfunction and related muscle disorders.
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BibTeX
@article{winant2026integrated,
title = {{Integrated Single-Myofibre Multi-Omics Correlates Inflammatory State to Myosin Energetics in ICU-Acquired Weakness.}},
author = {Alexandra M Winant and Roger Moreno-Justicia and Lucia Paolini and Wout J Claassen and Coen A C Ottenheijm and Atul S Deshmukh and Stefano Cattaneo and Simone Piva and Nicola Latronico and Robert A E Seaborne and Julien Ochala},
journal = {Journal of cachexia, sarcopenia and muscle},
year = {2026},
month = oct,
doi = {10.1002/jcsm.70407},
url = {https://europepmc.org/article/MED/42896625},
note = {CC BY},
}
RIS
TY - JOUR
TI - Integrated Single-Myofibre Multi-Omics Correlates Inflammatory State to Myosin Energetics in ICU-Acquired Weakness.
AU - Alexandra M Winant
AU - Roger Moreno-Justicia
AU - Lucia Paolini
AU - Wout J Claassen
AU - Coen A C Ottenheijm
AU - Atul S Deshmukh
AU - Stefano Cattaneo
AU - Simone Piva
AU - Nicola Latronico
AU - Robert A E Seaborne
AU - Julien Ochala
PY - 2026
DA - 2026/10/01
JO - Journal of cachexia, sarcopenia and muscle
DO - 10.1002/jcsm.70407
UR - https://europepmc.org/article/MED/42896625
AB - Background Skeletal muscle atrophy is a pervasive complication of critical illness that worsens survival and recovery, yet remains poorly explained by current clinical or molecular markers.Methods To directly connect disease-associated molecular states to the contractile machinery, this study combined sequential functional, transcriptomic and proteomic profiling of the same single human skeletal myofibres from critically ill patients in the intensive care unit with acquired weakness (ICU-AW) and controls. This integrated approach provides a framework for validating molecular signals directly within the cellular and biomechanical context.Results Differential expression analyses between control and ICU-AW myofibres show marked donor-level heterogeneity, with no differentially expressed features (FDR < 0.05). Ranked gene set enrichment analyses revealed distinct transcriptional and proteomic signatures between conditions, as well as a subtle yet conserved myofibre state enriched in ICU-AW, characterised by inflammatory and chemotactic gene programmes, intracellular structural remodelling and bioenergetic adaptation. Nineteen features were significantly (FDR < 0.05) altered at both RNA and protein levels from the same myofibre. Overall, these 19 overlapping features link an inflammatory transcriptional landscape to a proteomic shift toward mitochondrial and translational machinery, revealing a coordinated stress-adaptation programme with selective post-translational control in fibres from patients with ICU-AW. Further integration with the functional dataset revealed fibres in this state displayed selectively disrupted myosin dynamics, evidenced by prolonged ATP turnover time of myosin heads in their super-relaxed conformation, suggesting altered myosin energetics as a contributor to muscle dysfunction.Conclusions These findings define a discrete, disease-associated myofibre state and validate a proof-of-concept integrative single-fibre framework for connecting multi-omic heterogeneity to molecular motor function in complex human disease. The identification of coordinated transcriptomic and proteomic programmes, validated through functional measurement, suggests that targeting this fibre state may offer new therapeutic opportunities in ICU-acquired dysfunction and related muscle disorders.
SN - 2190-5991
SN - 2190-6009
ER -