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

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 dete...

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Published in:iScience 2023-03, Vol.26 (3), p.106074-106074, Article 106074
Main Authors: Gambardella, Jessica, Fiordelisi, Antonella, Cerasuolo, Federica Andrea, Buonaiuto, Antonietta, Avvisato, Roberta, Viti, Alessandro, Sommella, Eduardo, Merciai, Fabrizio, Salviati, Emanuela, Campiglia, Pietro, D’Argenio, Valeria, Parisi, Silvia, Bianco, Antonio, Spinelli, Letizia, Di Vaia, Eugenio, Cuocolo, Alberto, Pisani, Antonio, Riccio, Eleonora, Di Risi, Teodolinda, Ciccarelli, Michele, Santulli, Gaetano, Sorriento, Daniela, Iaccarino, Guido
Format: Article
Language:English
Subjects:
Cell biology
Cellular physiology
Health sciences
Pathophysiology
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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. [Display omitted] •FD mice and patients show intolerance to aerobic activity and lactate accumulation•A metabolic remodeling occurs in FD muscle with a glycolytic switch•miR-17 mediated HIF-1 upregulation is responsible for the Warburg effect in FD muscle•Exercise testing, blood lactate, and miR-17 are useful for monitoring FD Cell biology; Cellular physiology; Health sciences; Pathophysiology
ISSN:2589-0042
2589-0042
DOI:10.1016/j.isci.2023.106074