Valproate treatment induces lipid globule accumulation with ultrastructural abnormalities of mitochondria in skeletal muscle.
In skeletal muscle of seven children treated with valproic acid (VPA) microvesicular (0.05-2 microns) lipid droplets were observed between the myofibrils predominantly adjacent to the mitochondria. Most of the mitochondria showed ultrastructural abnormalities: several mitochondria were deformed and in several mitochondria abnormal configuration of cristae was observed. The size of some organelles reached the 10-20 microns length with normal diameter. The elongated mitochondria were located either in the long axis of the fibers or in the transverse direction near to the Z discs. In rats receiving valproic acid intraperitoneally for 14 days in daily dose of 100 mg/kg, steatosis developed in the liver, and focal lipid droplets could also be found in the skeletal muscle. The mitochondria of the rat liver appeared as normal, but in muscle the structure and organization of the cristae were disoriented. These observations show that treatment with valproate causes a kind of drug-induced mitochondrial cytopathy with microvesicular lipid deposition in the muscle. The lipid deposits are likely a result of the inhibited mitochondrial fatty acid oxidation. The formation of the abnormal mitochondrial structure could serve as background for the visible consequences of affected lipid metabolism.
Melegh
B
B
Department of Pediatrics, University Medical School of Pécs, Hungary.
Trombitás
K
K
D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects*; D002331:Carnitine / Q000172:deficiency; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D050356:Lipid Metabolism; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008931:Mitochondria, Muscle / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D009206:Myocardium / Q000648:ultrastructure; D011358:Product Surveillance, Postmarketing; D051381:Rats; D017207:Rats, Sprague-Dawley; D014635:Valproic Acid / Q000009:adverse effects*
D000927:Anticonvulsants; D014635:Valproic Acid; D002331:Carnitine