Experimental evidence and clinical implications of Warburg effect in the skeletal muscle of Fabry disease 2023 Gambardella et al

Highlights

• 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

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.

Open access, https://www.cell.com/iscience/fulltext/S2589-0042(23)00151-7