Revisiting insulin-stimulated hydrogen peroxide dynamics reveals a cytosolic reductive shift in skeletal muscle

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dc.contributor.authorHenríquez-Olguín, Carlos
dc.contributor.authorGallero, Samantha
dc.contributor.authorReddy, Anita
dc.contributor.authorPersson, Kaspar W.
dc.contributor.authorSchlabs, Farina L.
dc.contributor.authorVoldstedlund, Christian T.
dc.contributor.authorValentinaviciute, Gintare
dc.contributor.authorMeneses-Valdés, Roberto
dc.contributor.authorSigvardsen, Casper M.
dc.contributor.authorKiens, Bente
dc.contributor.authorChouchani, Edward T.
dc.contributor.authorRichter, Erik A.
dc.contributor.authorJensen, Thomas E.
dc.date.accessioned2025-12-01T15:48:08Z
dc.date.available2025-12-01T15:48:08Z
dc.date.issued2025-04-25
dc.description.abstractThe intracellular redox state is crucial for insulin responses in peripheral tissues. Despite the longstanding belief that insulin signaling increases hydrogen peroxide (H2O2) production leading to reversible oxidation of cysteine thiols, evidence is inconsistent and rarely involves human tissues. In this study, we systematically investigated insulin-dependent changes in subcellular H2O2 levels and reversible cysteine modifications across mouse and human skeletal muscle models. Utilizing advanced redox tools including genetically encoded H2O2 sensors and non-reducing immunoblotting we consistently observed no increase in subcellular H2O2 levels following insulin stimulation. Instead, stoichiometric cysteine proteome analyses revealed a selective pro-reductive shift in cysteine modifications affecting insulin transduction related proteins, including Cys179 on GSK3β and Cys416 on Ras and Rab Interactor 2 (RIN2). Our findings challenge the prevailing notion that insulin promotes H2O2 generation in skeletal muscle and suggest that an insulin-stimulated pro-reductive shift modulates certain aspects of insulin signal transduction.
dc.description.sponsorshipThe project was funded by a Synergy grant from the Novo Nordisk Foundation grant (no. #NNF20OC0063709), the Independent Research Fund Denmark (TEJ, Grant no. 9039-00029B), and the Lundbeck Foundation Ascending Investigator Grant (TEJ, no. R313-2019-643), CHO was generously supported by a postdoctoral grant from the Danish Diabetes Academy, funded by the Novo Nordisk Foundation (Grant no. NNF17SA0031406), We acknowledge the Core Facility for Integrated Microscopy, Fac
dc.identifier.citationRedox Biology, 82, (2025) p. 1-7.
dc.identifier.doihttps://doi.org/10.1016/j.redox.2025.103607
dc.identifier.issn2213-2317
dc.identifier.orcidhttps://orcid.org/0000-0002-9315-9365
dc.identifier.urihttps://hdl.handle.net/20.500.12254/7375
dc.language.isoen
dc.publisherElsevier
dc.rightsAtribución-NoComercial-CompartirIgual 3.0 Chile (CC BY-NC-SA 3.0 CL)
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/3.0/cl/
dc.subjectInsulin signaling
dc.subjectSkeletal muscle
dc.subjectRedox state
dc.titleRevisiting insulin-stimulated hydrogen peroxide dynamics reveals a cytosolic reductive shift in skeletal muscle
dc.typeArticle
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