WARBURG EFFECT CHARACTERIZES THE SKELETAL MUSCLE IN FABRY DISEASE: EXPERIMENTAL EVIDENCE AND CLINICAL IMPLICATIONS

Abstract

Objective: Skeletal muscle (SM) pain and fatigue are common in Fabry disease (FD), and strongly impact the patient's quality of life. Still, the SM in FD is poorly investigated. Although energetic alterations are reported in cells from FD patients, they have never been related to fatigue and pain. Given the pivotal relevance of energetics for SM health, we undertook the investigation of the SM. Design and method: We consistently observed a reduced tolerance to aerobic activity and lactate accumulation in FD-humanized mouse model and patients. Accordingly, in sedentary mouse FD SM we detected an increase in fast/glycolytic-fibers, mirrored by an upregulation of glycolytic enzymes and glucose-transporters Results: In fibroblasts derived from FD patients, we confirmed a high glycolytic-rate and accordingly, metabolomic/lipidomic-analysis revealed that lipids are underutilized as energetic fuel in FD-patients. In the quest for a tentative mechanism, we explored analogies with genetic myopathies, that show altered expression of energetic metabolism. Specifically, we explored HIF-1 upregulation and found it increased in FD mice and patients. Consistent with our previous screening of miRNAs associated with metabolic stress in FD, we observed a significant upregulation of miR-17 in FD patients and mice. Of note, miR-17 has been associated with cellular metabolic remodeling and HIF-1 up-regulation in different contexts. In our experimental setting, a specific antagomir targeting miR-17 was able to inhibit HIF-1 accumulation and revert metabolic-remodeling in FD-cells. Conclusions: Our findings unveil an anaerobic glycolytic-switch under normoxia, known as Warburg Effect, which is induced by miR-17-mediated-upregulation of HIF-1. The miR-17/HIF-1 pathway can be a new therapeutic target in FD, and Exercise-testing and blood lactate may become a new diagnostic and monitoring-tool in FD.