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 CiccarelliGaetano Santulli, Daniela Sorriento, Guido Iaccarino

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article number106074
Issue number3
StatePublished - Mar 17 2023


  • Cell biology
  • Cellular physiology
  • Health sciences
  • Pathophysiology

ASJC Scopus subject areas

  • General


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