Experimental evidence and clinical implications of Warburg effect in the skeletal muscle of Fabry disease

Jessica Gambardella; Antonella Fiordelisi; Federica Andrea Cerasuolo; Antonietta Buonaiuto; Roberta Avvisato; Alessandro Viti; Eduardo Sommella; Fabrizio Merciai; Emanuela Salviati; Pietro Campiglia; Valeria D'Argenio; Silvia Parisi; Antonio Bianco; Letizia Spinelli; Eugenio Di Vaia; Alberto Cuocolo; Antonio Pisani; Eleonora Riccio; Teodolinda Di Risi; Michele Ciccarelli; Gaetano Santulli; Daniela Sorriento; Guido Iaccarino

doi:10.1016/j.isci.2023.106074

Experimental evidence and clinical implications of Warburg effect in the skeletal muscle of Fabry disease

iScience. 2023 Jan 27;26(3):106074. doi: 10.1016/j.isci.2023.106074. eCollection 2023 Mar 17.

Authors

Jessica Gambardella^{1

2}, Antonella Fiordelisi¹, Federica Andrea Cerasuolo¹, Antonietta Buonaiuto¹, Roberta Avvisato¹, Alessandro Viti¹, Eduardo Sommella³, Fabrizio Merciai³, Emanuela Salviati³, Pietro Campiglia³, Valeria D'Argenio^{4

5}, Silvia Parisi⁶, Antonio Bianco², Letizia Spinelli², Eugenio Di Vaia¹, Alberto Cuocolo¹, Antonio Pisani⁷, Eleonora Riccio⁷, Teodolinda Di Risi⁷, Michele Ciccarelli⁸, Gaetano Santulli^{9

10}, Daniela Sorriento^{1

2}, Guido Iaccarino^{1

2}

Affiliations

¹ Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy.
² Interdepartmental Center of Research on Hypertension and Related Conditions (CIRIAPA), Federico II University, Naples, Italy.
³ Department of Pharmacy, University of Salerno, Salerno, Italy.
⁴ Department of Human Sciences and Quality of Life Promotion, San Raffaele Open University, Rome, Italy.
⁵ CEINGE- Advanced Biotechnologies, Naples, Italy.
⁶ Department of Molecular Medicine and Medical Biotechnologies, Federico II University, Naples, Italy.
⁷ Department of Public Health, Federico II University, Naples, Italy.
⁸ Department of Medicine and Surgery, University of Salerno, Salerno, Italy.
⁹ Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, NY, USA.
¹⁰ Department of Molecular Pharmacology, Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Einstein Institute for Neuroimmunology and Inflammation, Albert Einstein College of Medicine, New York, NY, USA.

Abstract

Skeletal muscle (SM) pain and fatigue are common in Fabry disease (FD). Here, we undertook the investigation of the energetic mechanisms related to FD-SM phenotype. A reduced tolerance to aerobic activity and lactate accumulation occurred in FD-mice and patients. Accordingly, in murine FD-SM we detected an increase in fast/glycolytic fibers, mirrored by glycolysis upregulation. In FD-patients, we confirmed a high glycolytic rate and the underutilization of lipids as fuel. In the quest for a tentative mechanism, we found HIF-1 upregulated in FD-mice and patients. This finding goes with miR-17 upregulation that is responsible for metabolic remodeling and HIF-1 accumulation. Accordingly, miR-17 antagomir inhibited HIF-1 accumulation, reverting the metabolic-remodeling in FD-cells. Our findings unveil a Warburg effect in FD, an anaerobic-glycolytic switch under normoxia induced by miR-17-mediated HIF-1 upregulation. Exercise-intolerance, blood-lactate increase, and the underlying miR-17/HIF-1 pathway may become useful therapeutic targets and diagnostic/monitoring tools in FD.

Keywords: Cell biology; Cellular physiology; Health sciences; Pathophysiology.