Display options
Cite
Arc-Chagnaud C, Salvador-Pascual A, Garcia-Dominguez E, et al. Glucose 6-P dehydrogenase delays the onset of frailty by protecting against muscle damage. J Cachexia Sarcopenia Muscle. 2021;12(6):1879-1896doi: 10.1002/jcsm.12792.
Arc-Chagnaud, C., Salvador-Pascual, A., Garcia-Dominguez, E., Olaso-Gonzalez, G., Correas, A. G., Serna, E., Brioche, T., Chopard, A., Fernandez-Marcos, P. J., Serrano, M., Serrano, A. L., Muñoz-Cánoves, P., Sebastiá, V., Viña, J., & Gomez-Cabrera, M. C. (2021). Glucose 6-P dehydrogenase delays the onset of frailty by protecting against muscle damage. Journal of cachexia, sarcopenia and muscle, 12(6), 1879-1896. https://doi.org/10.1002/jcsm.12792
Arc-Chagnaud, Coralie, et al. "Glucose 6-P dehydrogenase delays the onset of frailty by protecting against muscle damage." Journal of cachexia, sarcopenia and muscle vol. 12,6 (2021): 1879-1896. doi: https://doi.org/10.1002/jcsm.12792
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 Dec;12(6):1879-1896. doi: 10.1002/jcsm.12792. Epub 2021 Oct 26. PMID: 34704386; PMCID: PMC8718080.
Copy Download .nbib Format: NLM
Share it on

J Cachexia Sarcopenia Muscle. 2021 Dec;12(6):1879-1896. doi: 10.1002/jcsm.12792. Epub 2021 Oct 26.

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

Journal of cachexia, sarcopenia and muscle

Coralie Arc-Chagnaud, Andrea Salvador-Pascual, Esther Garcia-Dominguez, Gloria Olaso-Gonzalez, Angela G Correas, Eva Serna, Thomas Brioche, Angele Chopard, Pablo J Fernandez-Marcos, Manuel Serrano, Antonio L Serrano, Pura Muñoz-Cánoves, Vicente Sebastiá, Jose Viña, Mari Carmen Gomez-Cabrera

Affiliations

  1. Freshage Research Group, Department of Physiology, School of Medicine, University of Valencia, CIBERFES, Fundación Investigación Hospital Clínico Universitario/INCLIVA, Valencia, Spain.
  2. Department of Integrative Biology, University of California, Berkeley, CA, USA.
  3. INRAE, UMR866 Dynamique Musculaire et Métabolisme, Université de Montpellier, Montpellier, France.
  4. Metabolic Syndrome Group - BIOPROMET, Madrid Institute for Advanced Studies - IMDEA Food, CEI UAM+CSIC, Madrid, Spain.
  5. Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain.
  6. Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
  7. Department of Experimental and Health Sciences, University Pompeu Fabra and CIBERNED, Barcelona, Spain.
  8. Spanish National Center on Cardiovascular Research (CNIC), Madrid, Spain.
  9. Clinica Ypsilon de medicina física y rehabilitación, Valencia, Spain.

PMID: 34704386 PMCID: PMC8718080 DOI: 10.1002/jcsm.12792

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.

© 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.

Keywords: Aging; Antioxidant; Disability; Healthspan; Mitochondria; NADPH; Reactive oxygen species

References

  1. Biochem J. 1978 Jan 15;170(1):17-22 - PubMed
  2. J Cachexia Sarcopenia Muscle. 2019 Oct;10(5):1143-1145 - PubMed
  3. J Am Geriatr Soc. 2014 Jul;62(7):1324-8 - PubMed
  4. Nat Chem Biol. 2020 Jul;16(7):731-739 - PubMed
  5. Gerontology. 2015;61(5):407-15 - PubMed
  6. Free Radic Biol Med. 2018 Aug 20;124:358-363 - PubMed
  7. Nature. 2007 Jul 19;448(7151):375-9 - PubMed
  8. Aging Cell. 2020 Sep;19(9):e13193 - PubMed
  9. Cell Metab. 2015 Jul 7;22(1):86-99 - PubMed
  10. J Gerontol A Biol Sci Med Sci. 2016 Mar;71(3):333-9 - PubMed
  11. J Gerontol A Biol Sci Med Sci. 2014 Oct;69(10):1186-98 - PubMed
  12. Aging Cell. 2012 Oct;11(5):801-9 - PubMed
  13. FASEB J. 2006 Jul;20(9):1549-51 - PubMed
  14. Klin Wochenschr. 1957 Oct 15;35(20):1022-7 - PubMed
  15. Mol Aspects Med. 2016 Aug;50:88-108 - PubMed
  16. J Biol Chem. 2008 Nov 21;283(47):32492-9 - PubMed
  17. Nat Commun. 2016 Mar 15;7:10894 - PubMed
  18. Nature. 2014 Feb 20;506(7488):316-21 - PubMed
  19. J Cachexia Sarcopenia Muscle. 2021 Dec;12(6):1879-1896 - PubMed
  20. J Mol Cell Cardiol. 2010 Oct;49(4):625-38 - PubMed
  21. Oncotarget. 2016 Aug 9;7(32):50814-50815 - PubMed
  22. J Gerontol A Biol Sci Med Sci. 2008 Apr;63(4):391-8 - PubMed
  23. Lancet. 2008 Jan 5;371(9606):64-74 - PubMed
  24. Age (Dordr). 2014 Feb;36(1):117-27 - PubMed
  25. J Am Med Dir Assoc. 2016 May 1;17(5):426-33 - PubMed
  26. Nat Protoc. 2013 Sep;8(9):1660-9 - PubMed
  27. Geroscience. 2017 Apr;39(2):187-198 - PubMed
  28. J Cell Biol. 2007 Sep 10;178(6):1039-51 - PubMed
  29. J Gerontol A Biol Sci Med Sci. 2018 Sep 11;73(10):1323-1329 - PubMed
  30. Aging Cell. 2019 Feb;18(1):e12882 - PubMed
  31. Development. 2011 Sep;138(17):3639-46 - PubMed
  32. J Gerontol A Biol Sci Med Sci. 2001 Mar;56(3):M146-56 - PubMed
  33. Physiology (Bethesda). 2018 Jan 1;33(1):26-38 - PubMed
  34. Age (Dordr). 2012 Jun;34(3):669-79 - PubMed
  35. J Gerontol A Biol Sci Med Sci. 2015 Nov;70(11):1334-42 - PubMed
  36. Sci Rep. 2011;1:134 - PubMed
  37. Antioxid Redox Signal. 2020 Sep 10;33(8):570-579 - PubMed
  38. Spinal Cord. 2016 Oct;54(10):830-837 - PubMed
  39. Nat Commun. 2018 Oct 2;9(1):4045 - PubMed
  40. BMC Genomics. 2009 Apr 27;10:196 - PubMed
  41. Cell Stress Chaperones. 2006 Summer;11(2):116-28 - PubMed
  42. Development. 2011 Sep;138(17):3647-56 - PubMed
  43. Nat Commun. 2014 Jun 24;2:4172 - PubMed
  44. Physiol Rep. 2016 Nov;4(21): - PubMed
  45. J Cachexia Sarcopenia Muscle. 2018 Apr;9(2):335-347 - PubMed
  46. J Gerontol A Biol Sci Med Sci. 2017 Jul 1;72(7):885-891 - PubMed

Publication Types

Grant support