Phosphoproteomics of three exercise modalities identifies canonical signaling and C18ORF25 as an AMPK substrate regulating skeletal muscle function

Blazev, Ronnie; Carl, Christian S.; Ng, Yaan-Kit; Molendijk, Jeffrey; Voldstedlund, Christian T.; Zhao, Yuanyuan; Xiao, Di; Kueh, Andrew J.; Miotto, Paula M.; Haynes, Vanessa; Hardee, Justin P.; Chung, Jin D.; McNamara, James W.; Qian, Hongwei; Gregorevic, Paul; Oakhill, Jonathan S.; Herold, Marco J; Jensen, Thomas E.; Lisowski, Leszek; Lynch, Gordon S.; Dodd, Garron T.; Watt, Matthew J.; Yang, Pengyi; Kiens, Bente; Richter, Erik A.; Parker, Benjamin L.

doi:10.1016/j.cmet.2022.07.003

Cited by 40 publications

(82 citation statements)

References 106 publications

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“…An important difference between the current study and most of the previous ones is that patients with CAD underwent regular high-intensity exercise training as opposed to moderate-intensity continuous training. The two training modes likely stimulate different physiological pathways 26 27. Numerous studies have shown that high-intensity interval training is superior to moderate-intensity continuous training in terms of increasing peak oxygen uptake in patients with CAD28 29; but the impact on other parameters has not been thoroughly examined.…”

Section: Discussionmentioning

confidence: 99%

Haemostasis and fibrinolysis after regular high-intensity interval training in patients with coronary artery disease: a randomised controlled trial

et al. 2022

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IntroductionPatients with coronary artery disease (CAD) have prothrombotic changes compared with healthy individuals. Regular exercise reduces cardiovascular mortality in patients with stable CAD. However, the underlying mechanism for the beneficial effect is unknown. We investigated whether regular exercise would inhibit platelet aggregation and thrombin generation and increase fibrinolysis in patients with CAD.Materials and methodsPatients with CAD were randomised 1:1 to a supervised high-intensity exercise training programme or standard care for 12 weeks. Blood samples were obtained at baseline and after 6 and 12 weeks. Platelet aggregation was evaluated with the Multiplate Analyser, thrombin generation using the calibrated automated thrombogram and fibrinolysis employing a clot lysis assay.ResultsA total of 169 stable patients with CAD were randomised, and 142 patients (67±9 years, 83% males) completed the study; 64 in the exercise group and 78 in the standard care group. All but one patients received single antiplatelet therapy. From baseline to 12 weeks postintervention (Δ), no significant between-group differences were found in adenosine diphosphate-induced platelet aggregation (Δ−15 aggregation units (AU), AU×min, 95% CI −70 to 40 in the exercise group and Δ−26 AU×min, 95% CI −77 to 26 in the standard care group, p=0.44); endogenous thrombin potential (medians: Δ−5%, 95% CI −12 to 3 in the exercise group and Δ−6%, 95% CI −13 to 1 in the standard care group, p=0.26); nor in 50% clot lysis time (medians: Δ−9%, 95% CI −23 to 7 in the exercise group and Δ−17%, 95% CI −29 to −3 in the standard care group, p=0.60).ConclusionsTwelve weeks of high-intensity whole-body endurance exercise did not affect platelet aggregation, thrombin generation or fibrinolysis in patients with stable CAD.Trial registration numberNCT04268992.

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Section: Discussionmentioning

confidence: 99%

Haemostasis and fibrinolysis after regular high-intensity interval training in patients with coronary artery disease: a randomised controlled trial

et al. 2022

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“…However, there is currently no available human data to suggest it is a valid or reliable approach. Of interest, phosphoproteomic datasets of exercise have detected unchanged phosphorylation levels of AT-G16L1 at a different residue (serine 143) while S278 was not detected [61]. The following sections will highlight some of the recent developments in the use of ex vivo measurements of autophagy flux and will critically examine their advantages and limitations.…”

Section: Measuring Autophagy Flux In Humansmentioning

confidence: 99%

“…Using available transcriptomic [60] and phosphoproteomic [61,62] datasets, we have summarized the autophagy-regulated response to endurance exercise (▶Fig. 3-b).…”

Section: Endurance Exercisementioning

confidence: 99%

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Autophagy and Exercise: Current Insights and Future Research Directions

Botella,

Shaw,

Bishop

2023

Int J Sports Med

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Autophagy is a cellular process by which proteins and organelles are degraded inside the lysosome. Exercise is known to influence the regulation of autophagy in skeletal muscle. However, as gold standard techniques to assess autophagy flux in vivo are restricted to animal research, important gaps remain in our understanding of how exercise influences autophagy activity in humans. Using available datasets, we show how the gene expression profile of autophagy receptors and ATG8 family members differ between human and mouse skeletal muscle, providing a potential explanation for their differing exercise-induced autophagy responses. Furthermore, we provide a comprehensive view of autophagy regulation following exercise in humans by summarising human transcriptomic and phosphoproteomic datasets that provide novel targets of potential relevance. These newly identified phosphorylation sites may provide an explanation as to why both endurance and resistance exercise lead to an exercise-induced reduction in LC3B-II, while possibly divergently regulating autophagy receptors, and, potentially, autophagy flux. We also provide recommendations to use ex vivo autophagy flux assays to better understand the influence of exercise, and other stimuli, on autophagy regulation in humans. This review provides a critical overview of the field and points towards novel research areas of autophagy regulation following exercise in humans.

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“…Acute exercise study: These samples were acquired from a previous study. Please see 6 for further information.…”

Section: Human Experimentsmentioning

confidence: 99%

The Rho GTPase Rac1 mediates exercise training adaptations

Raun,

Henriquez-Olguín,

Frank

et al. 2023

Preprint

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Exercise training elicits tremendous health benefits; however, the molecular underpinnings are poorly understood. As one of the most regulated groups of proteins following acute exercise in human muscle, Rho GTPases are unexplored candidates for mediating the beneficial effects of exercise. The Rho GTPase Rac1 was activated during multiple exercise modalities and remained elevated hours after resistance exercise in human muscle. Inducible muscle-specific Rac1 knockout (Rac1 imKO) mice, displayed attenuated muscle protein synthesis, glycogen resynthesis and p38 MAPK signaling in recovery from contractions. Exercise training upregulated Rac1 protein content in human and mouse muscle. Overexpression of hyperactive Rac1 elevated reactive oxidant species production during exercise yet did not induce a trained muscle phenotype. In Rac1 imKO mice, the improvements in running capacity and muscle mass after exercise training were diminished. Using gain- and loss-of-function mouse models and human muscle biopsies, we identify Rac1 as a regulator of exercise training adaptions.HighlightsVarious exercise modalities activate Rac1 signaling in human skeletal muscle.HSP27, MNK1, and CREB are Rac1-dependent contraction-responsive targets in muscle.Post-contraction protein synthesis requires Rac1 but not NOX2.Rac1-NOX2 signaling is necessary for post-contraction glycogen resynthesis.Exercise training increases Rac1 protein content in human and mouse muscles.Rac1 mediates critical adaptations to exercise training.

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Phosphoproteomics of three exercise modalities identifies canonical signaling and C18ORF25 as an AMPK substrate regulating skeletal muscle function

Cited by 40 publications

References 106 publications

Haemostasis and fibrinolysis after regular high-intensity interval training in patients with coronary artery disease: a randomised controlled trial

Haemostasis and fibrinolysis after regular high-intensity interval training in patients with coronary artery disease: a randomised controlled trial

Autophagy and Exercise: Current Insights and Future Research Directions

The Rho GTPase Rac1 mediates exercise training adaptations

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