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Network model of skeletal muscle cell signalling predicts differential responses to endurance and resistance exercise training
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Issue Date
2024-04-21Author
Fowler, Annabelle
Knaus, Katherine R
Khuu, Stephanie
Khalilimeybodi, Ali
Schenk, Simon
Ward, Samuel R.
Fry, Andrew C.
Rangamani, Padmini
McCulloch, Andrew D.
Publisher
The Physiological Society
Type
Article
Article Version
Scholarly/refereed, publisher version
Rights
Copyright © 2024 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.
This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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Show full item recordAbstract
Exercise‐induced muscle adaptations vary based on exercise modality and intensity. We constructed a signalling network model from 87 published studies of human or rodent skeletal muscle cell responses to endurance or resistance exercise in vivo or simulated exercise in vitro. The network comprises 259 signalling interactions between 120 nodes, representing eight membrane receptors and eight canonical signalling pathways regulating 14 transcriptional regulators, 28 target genes and 12 exercise‐induced phenotypes. Using this network, we formulated a logic‐based ordinary differential equation model predicting time‐dependent molecular and phenotypic alterations following acute endurance and resistance exercises. Compared with nine independent studies, the model accurately predicted 18/21 (85%) acute responses to resistance exercise and 12/16 (75%) acute responses to endurance exercise. Detailed sensitivity analysis of differential phenotypic responses to resistance and endurance training showed that, in the model, exercise regulates cell growth and protein synthesis primarily by signalling via mechanistic target of rapamycin, which is activated by Akt and inhibited in endurance exercise by AMP‐activated protein kinase. Endurance exercise preferentially activates inflammation via reactive oxygen species and nuclear factor κB signalling. Furthermore, the expected preferential activation of mitochondrial biogenesis by endurance exercise was counterbalanced in the model by protein kinase C in response to resistance training. This model provides a new tool for investigating cross‐talk between skeletal muscle signalling pathways activated by endurance and resistance exercise, and the mechanisms of interactions such as the interference effects of endurance training on resistance exercise outcomes.
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Citation
Fowler A, Knaus KR, Khuu S, Khalilimeybodi A, Schenk S, Ward SR, Fry AC, Rangamani P, McCulloch AD. Network model of skeletal muscle cell signalling predicts differential responses to endurance and resistance exercise training. Exp Physiol. 2024 Jun;109(6):939-955. doi: 10.1113/EP091712. Epub 2024 Apr 21. PMID: 38643471; PMCID: PMC11140181
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