Résumé :
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Communication n° 81. Inborn errors of mitochondrial fatty acid oxidation (FAO) often lead to metabolic myopathy presenting as muscle weakness, exercise intolerance and episodes of myoglobinuria. This typical phenotype is likely due to insufficient residual activity of mutated enzyme in skeletal muscle, hampering the use of fatty acids under conditions of high energy demand. Our recent data show that pharmacological stimulation of PPARs (Peroxisome Proliferator Activated Receptors), a group of nuclear receptors controlling lipid metabolism, provides an efficient way to restore fatty acid utilization in cells harboring FAO defects. Thus, exposure of myoblasts from Carnitine Palmitoyl Transferase 2 (CPT2) deficient patients to high affinity agonists of various PPAR isoforms revealed that stimulation of CPT2 gene expression (+70%) and enzyme activity (+75%), and normalization of palmitate oxidation was obtained in response to PPAR delta activation. Similar results were obtained after treatment of myoblasts by bezafibrate, a hypolipidemic drug acting as a pan-agonist of PPARs. Analysis by tandem mass spectrometry showed that bezafibrate prevented the deleterious accumulation of acylcarnitines observed in untreated CPT2-deficient myoblasts. Further experiments were conducted in fibroblasts from patients presenting with myopathic form of VLCAD (Very Long Chain AcylCoA Dehydrogenase) deficiency. The results show that bezafibrate, as well as fenofibrate another hypolipidemic drug, were able to restore normal FAO in deficient cells. This was related to drug-induced stimulation of VLCAD gene expression (+90%) leading to a spectacular increase in residual VLCAD enzyme activity (x2,5). Quantitative PCR studies identified a set of FAO enzyme genes also markedly stimulated in response to fibrates. These pre-clinical data define new therapeutic applications of PPAR agonists and provide a common rationale for studying correction of various FAO defects responsible for metabolic myopathies.
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