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Publications

Journal Article Ppublish

PubMed: 39514761 DOI: 10.1182/bloodadvances.2024013968

Increased exercise tolerance in humanized G6PD-deficient mice.

Blood Adv 9(2):321-334

Authors: Francesca I Cendali, Christina Lisk, Monika Dzieciatkowska, Ian S LaCroix, Julie A Reisz, Julie Harral, Daniel Stephenson, Ariel M Hay, Eric P Wartchow, Anza Darehshouri, Karolina H Dziewulska-Cronk, Paul W Buehler, Philip J Norris, Xutao Deng, Michael P Busch, Eric J Earley, Grier P Page, Kirk C Hansen, James C Zimring, David C Irwin, Travis Nemkov, Angelo D'Alessandro

Affiliations

  • Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO.
  • Department of Medicine, Cardiovascular and Pulmonary Research Laboratory, University of Colorado Anschutz Medical Campus, Aurora, CO.
  • Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO.
  • Department of Pathology, University of Virginia School of Medicine, Charlottesville, VA.
  • Department of Pathology, Children's Hospital Colorado, Aurora, CO.
  • Electron Microscopy Core Facility, University of Colorado Anschutz Medical Campus, Aurora, CO.
  • Department of Pediatrics, Center for Blood Oxygen Transport, University of Maryland School of Medicine, Baltimore, MD.
  • Department of Pathology, University of Maryland School of Medicine, Baltimore, MD.
  • Vitalant Research Institute, San Francisco, CA.
  • Research Triangle Institute International, Atlanta, GA.

Abstract

Glucose-6-phosphate dehydrogenase (G6PD) deficiency affects 500 million people globally, affecting red blood cell (RBC) antioxidant pathways and increasing susceptibility to hemolysis under oxidative stress. Despite the systemic generation of reactive oxygen species during exercise, the effects of exercise on individuals with G6PD deficiency remain poorly understood This study used humanized mouse models expressing the G6PD Mediterranean variant (S188F, with 10% enzymatic activity) to investigate exercise performance and molecular outcomes. Surprisingly, despite decreased enzyme activity, G6PD-deficient mice have faster critical speed than mice expressing human canonical G6PD. After exercise, deficient mice did not exhibit differences in RBC morphology or hemolysis, but had improved cardiac function, including cardiac output, stroke volume, sarcomere length, and mitochondrial content. Proteomics analyses of cardiac and skeletal muscles (gastrocnemius, soleus) from G6PD-deficient compared with sufficient mice revealed improvements in mitochondrial function and increased protein turnover via ubiquitination, especially for mitochondrial and structural myofibrillar proteins. Mass spectrometry-based metabolomics revealed alterations in energy metabolism and fatty acid oxidation. These findings challenge the traditional assumptions regarding hemolytic risk during exercise in G6PD deficiency, suggesting a potential metabolic advantage in exercise performance for individuals carrying noncanonical G6PD variants.

MeSH

Exercise, Exercise Tolerance, Hemolysis, Hematologic Diseases