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Decreased Fatty Acid ß-Oxidation in Riboflavin-Responsive, Multiple Acylcoenzyme A Dehydrogenase-Deficient Patients Is Associated with an Increase in Uncoupling Protein-3

Department of Medical Biochemistry, University of Geneva Medical Center (A.P.R., E.S., G.G., J.-P.G., P.M.), 1206 Geneva, Switzerland; Departments of Human Biology (P.S., E.K.) and Movement Sciences (M.K.C.H., G.S.), Maastricht University, 6200 Maastricht, The Netherlands; Institute for International Health, University of Sydney (S.K.L.), 2042 Sydney, Australia; and Department of Neurological Science, University of Padova (D.B., M.C., C.A., L.V.), 35129 Padova, Italy

Address all correspondence and requests for reprints to: Dr. Aaron P. Russell, Clinique Romande de Réadaptation, Case Postale 352, Avenue Gd-Champsec 90, 1951 Sion, Switzerland. E-mail: aaron.russell{at}crr-suva.ch.

Riboflavin-responsive, multiple acylcoenzyme A dehydrogenase deficiency (RR-MAD), a lipid storage myopathy, is characterized by, among others, a decrease in fatty acid (FA) ß-oxidation capacity. Muscle uncoupling protein 3 (UCP3) is up-regulated under conditions that either increase the levels of circulating free FA and/or decrease FA ß-oxidation. Using a relatively large cohort of seven RR-MAD patients, we aimed to better characterize the metabolic disturbances of this disease and to explore the possibility that it might increase UCP3 expression. A battery of biochemical and molecular tests were performed, which demonstrated decreases in FA ß-oxidation and in the activities of respiratory chain complexes I and II. These metabolic alterations were associated with increases of 3.1- and 1.7-fold in UCP3 mRNA and protein expression, respectively. All parameters were restored to control values after riboflavin treatment. We postulate that the up-regulation of UCP3 in RR-MAD is due to the accumulation of muscle FA/acylCoA. RR-MAD is an optimal model to support the hypothesis that UCP3 is involved in the outward translocation of an excess of FA from the mitochondria and to show that, in humans, the effects of FA on UCP3 expression are direct and independent of fatty acid ß-oxidation.

This work was supported by grants from the Helen M. Schutt Trust, Office Féderal du Sport Macolin, Fonds Eugne Rapin, the Fondation du Centenaire de la Société Suisse d’Assurances Générales sur la vie Humaine pour la Santé Publique et les Recherches Médicales, and the Sir Jules Thorn Charitable Overseas Trust (to A.P.R.); Swiss National Science Foundation Grant 31-54306.98; the Fondation Suisse de Recherche sur les Maladies Musculaires; a grant from The Netherlands Organization for Scientific Research (to P.S.); and Telethon Grants 1205 and TF003Y01 (for tissue bank to C.A.).

Abbreviations: CoA, Coenzyme A; FA, fatty acid; FFA, free fatty acids; IMCL, intramyocellular lipid; RR-MAD, riboflavin-responsive, multiple acylcoenzyme A dehydrogenase deficiency; UCP, uncoupling protein.

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