TY - JOUR
T1 - Experimental evidence and clinical implications of Warburg effect in the skeletal muscle of Fabry disease
AU - Gambardella, Jessica
AU - Fiordelisi, Antonella
AU - Cerasuolo, Federica Andrea
AU - Buonaiuto, Antonietta
AU - Avvisato, Roberta
AU - Viti, Alessandro
AU - Sommella, Eduardo
AU - Merciai, Fabrizio
AU - Salviati, Emanuela
AU - Campiglia, Pietro
AU - D'Argenio, Valeria
AU - Parisi, Silvia
AU - Bianco, Antonio
AU - Spinelli, Letizia
AU - Di Vaia, Eugenio
AU - Cuocolo, Alberto
AU - Pisani, Antonio
AU - Riccio, Eleonora
AU - Di Risi, Teodolinda
AU - Ciccarelli, Michele
AU - Santulli, Gaetano
AU - Sorriento, Daniela
AU - Iaccarino, Guido
N1 - Publisher Copyright:
© 2023 The Authors
PY - 2023/3/17
Y1 - 2023/3/17
N2 - 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.
AB - 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.
KW - Cell biology
KW - Cellular physiology
KW - Health sciences
KW - Pathophysiology
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U2 - 10.1016/j.isci.2023.106074
DO - 10.1016/j.isci.2023.106074
M3 - Article
AN - SCOPUS:85148733626
SN - 2589-0042
VL - 26
JO - iScience
JF - iScience
IS - 3
M1 - 106074
ER -