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Glucose 6-P dehydrogenase delays the onset of frailty by protecting against muscle damage

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dc.contributor.author Arc-Chagnaud, Coralie
dc.contributor.author Salvador-Pascual, Andrea
dc.contributor.author Garcia-Dominguez, Esther
dc.contributor.author Olaso-Gonzalez, Gloria
dc.contributor.author Correas, Angela G.
dc.contributor.author Serna, Eva
dc.contributor.author Brioche, Thomas
dc.contributor.author Chopard, Angele
dc.contributor.author Fernandez-Marcos, Pablo J.
dc.contributor.author Serrano, Manuel
dc.contributor.author Serrano, Antonio L.
dc.contributor.author Muñoz Cánoves, Pura, 1962-
dc.contributor.author Sebastiá, Vicente
dc.contributor.author Viña, Jose
dc.contributor.author Gomez-Cabrera, Mari Carmen
dc.date.accessioned 2021-12-15T07:30:28Z
dc.date.available 2021-12-15T07:30:28Z
dc.date.issued 2021
dc.identifier.citation Arc-Chagnaud C, Salvador-Pascual A, Garcia-Dominguez E, Olaso-Gonzalez G, Correas AG, Serna E, Brioche T, Chopard A, Fernandez-Marcos PJ, Serrano M, Serrano AL, Muñoz-Cánoves P, Sebastiá V, Viña J, Gomez-Cabrera MC. Glucose 6-P dehydrogenase delays the onset of frailty by protecting against muscle damage. J Cachexia Sarcopenia Muscle. 2021;12(6):1879-96. DOI: 10.1002/jcsm.12792
dc.identifier.issn 2190-5991
dc.identifier.uri http://hdl.handle.net/10230/49212
dc.description.abstract Background: Frailty is a major age-associated syndrome leading to disability. Oxidative damage plays a significant role in the promotion of frailty. The cellular antioxidant system relies on reduced nicotinamide adenine dinucleotide phosphate (NADPH) that is highly dependent on glucose 6-P dehydrogenase (G6PD). The G6PD-overexpressing mouse (G6PD-Tg) is protected against metabolic stresses. Our aim was to examine whether this protection delays frailty. Methods: Old wild-type (WT) and G6PD-Tg mice were evaluated longitudinally in terms of frailty. Indirect calorimetry, transcriptomic profile, and different skeletal muscle quality markers and muscle regenerative capacity were also investigated. Results: The percentage of frail mice was significantly lower in the G6PD-Tg than in the WT genotype, especially in 26-month-old mice where 50% of the WT were frail vs. only 13% of the Tg ones (P < 0.001). Skeletal muscle transcriptomic analysis showed an up-regulation of respiratory chain and oxidative phosphorylation (P = 0.009) as well as glutathione metabolism (P = 0.035) pathways in the G6PD-Tg mice. Accordingly, the Tg animals exhibited an increase in reduced glutathione (34.5%, P < 0.01) and a decrease on its oxidized form (-69%, P < 0.05) and in lipid peroxidation (4-HNE: -20.5%, P < 0.05). The G6PD-Tg mice also showed reduced apoptosis (BAX/Bcl2: -25.5%, P < 0.05; and Bcl-xL: -20.5%, P < 0.05), lower levels of the intramuscular adipocyte marker FABP4 (-54.7%, P < 0.05), and increased markers of mitochondrial content (COX IV: 89.7%, P < 0.05; Grp75: 37.8%, P < 0.05) and mitochondrial OXPHOS complexes (CII: 81.25%, P < 0.01; CIII: 52.5%, P < 0.01; and CV: 37.2%, P < 0.05). Energy expenditure (-4.29%, P < 0.001) and the respiratory exchange ratio were lower (-13.4%, P < 0.0001) while the locomotor activity was higher (43.4%, P < 0.0001) in the 20-month-old Tg, indicating a major energetic advantage in these mice. Short-term exercise training in young C57BL76J mice induced a robust activation of G6PD in skeletal muscle (203.4%, P < 0.05), similar to that achieved in the G6PD-Tg mice (142.3%, P < 0.01). Conclusions: Glucose 6-P dehydrogenase deficiency can be an underestimated risk factor for several human pathologies and even frailty. By overexpressing G6PD, we provide the first molecular model of robustness. Because G6PD is regulated by pharmacological and physiological interventions like exercise, our results provide molecular bases for interventions that by increasing G6PD will delay the onset of frailty.
dc.description.sponsorship This work was supported by Instituto de Salud Carlos III CB16/10/00435 (CIBERFES) (PID2019-110906RB-I00/AEI/10.13039/501100011033) from the Spanish Ministry of Innovation and Science; 109_RESIFIT from Fundación General CSIC; PROMETEO/2019/097 de ‘Consellería, de Sanitat de la Generalitat Valenciana’ and EU Funded H2020-DIABFRAIL-LATAM (Ref: 825546); European Joint Programming Initiative ‘A Healthy Diet for a Healthy Life’ (JPI HDHL); and the ERA-NET Cofund ERA-HDHL (GA No. 696295 of the EU Horizon 2020 Research and Innovation Programme). Part of the equipment employed in this work has been funded by Generalitat Valenciana and co-financed with ERDF funds (OP ERDF of Comunitat Valenciana 2014–2020). Work in the laboratory of P.J.F.-M. was funded by the FBBVA and the Ramón Areces Foundations. Work in the laboratory of P.M.-C. and A.L.S was funded by by MWRF and Fundació La Marató/TV3-80/19-202021 to P.M.C. and Fundació La Marató de TV3 (Project 202033 to A.L.S.), MINECO-Spain (RTI2018-096068), ERC-2016-AdG-741966, LaCaixa-HEALTH-HR17-00040, MDA, UPGRADE-H2020-825825, AFM, and DPP-Spain; María-de-Maeztu-Program for Units of Excellence to UPF (MDM-2014-0370); and Severo-Ochoa-Program for Centers of Excellence to CNIC (SEV-2015-0505). A.S.-P. was supported by a fellowship from the Spanish ‘Ministerio de Educación, Cultura y Deporte’, award FPU 14/00098.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher Wiley
dc.relation.ispartof J Cachexia Sarcopenia Muscle. 2021;12(6):1879-96
dc.rights © 2021 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.title Glucose 6-P dehydrogenase delays the onset of frailty by protecting against muscle damage
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1002/jcsm.12792
dc.subject.keyword Aging
dc.subject.keyword Antioxidant
dc.subject.keyword Disability
dc.subject.keyword Healthspan
dc.subject.keyword Mitochondria
dc.subject.keyword NADPH
dc.subject.keyword Reactive oxygen species
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/825546
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/696295
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/741966
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/825825
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion

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