iScience (Mar 2023)
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
Affiliations
- Jessica Gambardella
- Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy; Interdepartmental Center of Research on Hypertension and Related Conditions (CIRIAPA), Federico II University, Naples, Italy
- Antonella Fiordelisi
- Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy
- Federica Andrea Cerasuolo
- Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy
- Antonietta Buonaiuto
- Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy
- Roberta Avvisato
- Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy
- Alessandro Viti
- Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy
- Eduardo Sommella
- Department of Pharmacy, University of Salerno, Salerno, Italy
- Fabrizio Merciai
- Department of Pharmacy, University of Salerno, Salerno, Italy
- Emanuela Salviati
- Department of Pharmacy, University of Salerno, Salerno, Italy
- Pietro Campiglia
- Department of Pharmacy, University of Salerno, Salerno, Italy
- Valeria D’Argenio
- Department of Human Sciences and Quality of Life Promotion, San Raffaele Open University, Rome, Italy; CEINGE- Advanced Biotechnologies, Naples, Italy
- Silvia Parisi
- Department of Molecular Medicine and Medical Biotechnologies, Federico II University, Naples, Italy
- Antonio Bianco
- Interdepartmental Center of Research on Hypertension and Related Conditions (CIRIAPA), Federico II University, Naples, Italy
- Letizia Spinelli
- Interdepartmental Center of Research on Hypertension and Related Conditions (CIRIAPA), Federico II University, Naples, Italy
- Eugenio Di Vaia
- Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy
- Alberto Cuocolo
- Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy
- Antonio Pisani
- Department of Public Health, Federico II University, Naples, Italy
- Eleonora Riccio
- Department of Public Health, Federico II University, Naples, Italy
- Teodolinda Di Risi
- Department of Public Health, Federico II University, Naples, Italy
- Michele Ciccarelli
- Department of Medicine and Surgery, University of Salerno, Salerno, Italy
- Gaetano Santulli
- 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; 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
- Daniela Sorriento
- Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy; Interdepartmental Center of Research on Hypertension and Related Conditions (CIRIAPA), Federico II University, Naples, Italy
- Guido Iaccarino
- Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy; Interdepartmental Center of Research on Hypertension and Related Conditions (CIRIAPA), Federico II University, Naples, Italy; Corresponding author
- Journal volume & issue
-
Vol. 26,
no. 3
p. 106074
Abstract
Summary: 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.
