Altered fiber type distribution, reduced lipid transport, and decreased carnitine concentrations in skeletal muscle of subjects with fatty acid oxidation disorders

Oleg Varlamov1, Cary O. Harding,2, Charles Roberts Jr1, Jon Gangoiti3, Bruce Barhsop3, Mike Lasarev4, Svyatoslav Kleshchev1, Jonathan Q. Purnell5, and Melanie B. Gillingham2

Corresponding author: Oleg Varlamov, M.D., Ph.D.; 503-346-5377;

1Oregon National Primate Research Center, 2Department of Molecular & Medical Genetics,4Oregon Institute of Occupational Health Sciences, 5The Knight Cardiovascular Institute at Oregon Health & Science University, Portland, Oregon, 3Biochemical Genetics Program, University of California San Diego, La Jolla, CA, USA

As part of a study of the role of mitochondrial fatty acid oxidation in regulating glucose disposal, we recruited a cohort of patients with confirmed FAO disorders (FAOD, n=9), including carnitine palmitoyltransferase-2, very long-chain acylCoA dehydrogenase, trifunctional protein or long-chain 3-hydroxyacylCoA dehydrogenase, and medium chain acylCoA dehydrogenase deficiencies into a randomized, crossover study. Each FAOD patient and a normal control (n=5) were subjected to two hyperinsulinemic-euglycemic clamps with either concurrent infusion of intralipid (high fat) or glycerol (control). At the end of each clamp, vastus lateralis biopsies were collected and analyzed histologically. We determined muscle fiber type distribution, CD36 lipid transporter protein expression, and insulin-stimulated uptake of fluorescently labelled free fatty acids (BODIPY FFAs) in skeletal muscle explants ex vivo using confocal microscopy. Metabolomic analysis of lipid and water-soluble compounds in frozen muscle tissue was measured using liquid chromatography-electrospray tandem mass spectrometry.

FAOD subjects demonstrated a significantly higher proportion of type 2a fast-twitch fibers compared to control subjects (p<0.032). CD36 expression was significantly decreased in skeletal muscle of FAOD subjects. The uptake of intramyocellular BODIPY lipids in skeletal muscle fibers of the FAOD subjects were also significantly lower than that of the control subjects under both glycerol and intralipid conditions. The levels of intramyocellular carnitine, acetylcarnitine, butyrylcarnitine and valerylcarnitine were reduced in FAOD subjects under both glycerol and intralipid conditions but there was no difference in long-chain acylcarnitine species between muscle of subjects with FAOD or controls. These studies confirm that muscle fibers of patients with FAOD are enriched with fast-twitch fibers and demonstrate, for the first time, that skeletal muscle FFA transport and incorporation into lipid stores are reduced. Remarkably, long-chain acylcarnitines are not increased in skeletal muscle among subjects with FAOD compared to controls under anabolic conditions. We are currently conducting additional studies      to test whether the downregulation of skeletal muscle lipid metabolism is associated   with a compensatory increase in circulating free fatty acids and acylcarnitines during periods of anabolism, such as during glucose and insulin infusions, and if this is associated with an increase of glucose flux in the skeletal muscle of FAOD patients.

Funded by R01DK102813

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