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The high incidence of G6PD deficiency may reflect an evolutionary adaptation to the widespread prevalence of malaria, as G6PD-deficient red blood cells (RBCs) are hostile to the malaria parasites that infect humans. Although medical interest in this enzyme deficiency has been mainly focused on RBCs, more recent evidence suggests that there are broader implications for G6PD deficiency in health, including in skeletal muscle diseases. G6PD catalyzes the rate-limiting step in the pentose phosphate pathway (PPP), which provides the precursors of nucleotide synthesis for DNA replication as well as reduced nicotinamide adenine dinucleotide phosphate (NADPH). NADPH is involved in the detoxification of cellular reactive oxygen species (ROS) and de novo lipid synthesis. An association between increased PPP activity and the stimulation of cell growth has been reported in different tissues including the skeletal muscle, liver, and kidney. PPP activity is increased in skeletal muscle during embryogenesis, denervation, ischemia, mechanical overload, the injection of myonecrotic agents, and physical exercise. In fact, the highest relative increase in the activity of skeletal muscle enzymes after one bout of exhaustive exercise is that of G6PD, suggesting that the activation of the PPP occurs in skeletal muscle to provide substrates for muscle repair. The age-associated loss in muscle mass and strength leads to a decrease in G6PD activity and protein content in skeletal muscle. G6PD overexpression in Drosophila Melanogaster and mice protects against metabolic stress, oxidative damage, and age-associated functional decline, and results in an extended median lifespan. This review discusses whether the well-known positive effects of exercise training in skeletal muscle are mediated through an increase in G6PD.<\/jats:p>","DOI":"10.3390\/cells11193041","type":"journal-article","created":{"date-parts":[[2022,9,28]],"date-time":"2022-09-28T20:58:47Z","timestamp":1664398727000},"page":"3041","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Glucose 6-P Dehydrogenase\u2014An Antioxidant Enzyme with Regulatory Functions in Skeletal Muscle during Exercise"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6276-4944","authenticated-orcid":false,"given":"Esther","family":"Garc\u00eda-Dom\u00ednguez","sequence":"first","affiliation":[{"name":"Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia and CIBERFES, Fundaci\u00f3n Investigaci\u00f3n Hospital Cl\u00ednico Universitario\/INCLIVA, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0585-9565","authenticated-orcid":false,"given":"Aitor","family":"Carretero","sequence":"additional","affiliation":[{"name":"Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia and CIBERFES, Fundaci\u00f3n Investigaci\u00f3n Hospital Cl\u00ednico Universitario\/INCLIVA, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aurora","family":"Vi\u00f1a-Almunia","sequence":"additional","affiliation":[{"name":"Centro de Salud San Isidro, Consorcio Hospital General Universitario de Valencia, 46014 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9488-8159","authenticated-orcid":false,"given":"Julio","family":"Domenech-Fernandez","sequence":"additional","affiliation":[{"name":"Health Care Department Arnau-Lliria, Servicio de Cirug\u00eda Ortop\u00e9dica y Traumatolog\u00eda, Hospital Arnau de Vilanova y Hospital de Liria, 46015 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3138-3513","authenticated-orcid":false,"given":"Gloria","family":"Olaso-Gonzalez","sequence":"additional","affiliation":[{"name":"Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia and CIBERFES, Fundaci\u00f3n Investigaci\u00f3n Hospital Cl\u00ednico Universitario\/INCLIVA, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9709-0089","authenticated-orcid":false,"given":"Jose","family":"Vi\u00f1a","sequence":"additional","affiliation":[{"name":"Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia and CIBERFES, Fundaci\u00f3n Investigaci\u00f3n Hospital Cl\u00ednico Universitario\/INCLIVA, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4000-1684","authenticated-orcid":false,"given":"Mari Carmen","family":"Gomez-Cabrera","sequence":"additional","affiliation":[{"name":"Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia and CIBERFES, Fundaci\u00f3n Investigaci\u00f3n Hospital Cl\u00ednico Universitario\/INCLIVA, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/0003-9861(59)90024-4","article-title":"The oxidative pentose phosphate cycle. 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