title: In vivo, fatty acid translocase (CD36) critically regulates skeletal muscle fuel selection, exercise performance, and training-induced adaptation of fatty acid oxidation.
abstract: For ~40 years it has been widely accepted that (i) the exercise-induced increase in muscle fatty acid oxidation (FAO) is dependent on the increased delivery of circulating fatty acids, and (ii) exercise training-induced FAO up-regulation is largely attributable to muscle mitochondrial biogenesis. These long standing concepts were developed prior to the recent recognition that fatty acid entry into muscle occurs via a regulatable sarcolemmal CD36-mediated mechanism. We examined the role of CD36 in muscle fuel selection under basal conditions, during a metabolic challenge (exercise), and after exercise training. We also investigated whether CD36 overexpression, independent of mitochondrial changes, mimicked exercise training-induced FAO up-regulation. Under basal conditions CD36-KO versus WT mice displayed reduced fatty acid transport (-21%) and oxidation (-25%), intramuscular lipids (less than or equal to -31%), and hepatic glycogen (-20%); but muscle glycogen, VO(2max), and mitochondrial content and enzymes did not differ. In acutely exercised (78% VO(2max)) CD36-KO mice, fatty acid transport (-41%), oxidation (-37%), and exercise duration (-44%) were reduced, whereas muscle and hepatic glycogen depletions were accelerated by 27-55%, revealing 2-fold greater carbohydrate use. Exercise training increased mtDNA and β-hydroxyacyl-CoA dehydrogenase similarly in WT and CD36-KO muscles, but FAO was increased only in WT muscle (+90%). Comparable CD36 increases, induced by exercise training (+44%) or by CD36 overexpression (+41%), increased FAO similarly (84-90%), either when mitochondrial biogenesis and FAO enzymes were up-regulated (exercise training) or when these were unaltered (CD36 overexpression). Thus, sarcolemmal CD36 has a key role in muscle fuel selection, exercise performance, and training-induced muscle FAO adaptation, challenging long held views of mechanisms involved in acute and adaptive regulation of muscle FAO.
authors.affiliation: Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario N1G 2W1, Canada.
authors.forename: Jay T
authors.initials: JT
authors.lastname: McFarlan
authors.forename: Yuko
authors.initials: Y
authors.lastname: Yoshida
authors.forename: Swati S
authors.initials: SS
authors.lastname: Jain
authors.forename: Xioa-Xia
authors.initials: XX
authors.lastname: Han
authors.forename: Laelie A
authors.initials: LA
authors.lastname: Snook
authors.forename: James
authors.initials: J
authors.lastname: Lally
authors.forename: Brennan K
authors.initials: BK
authors.lastname: Smith
authors.forename: Jan F C
authors.initials: JF
authors.lastname: Glatz
authors.forename: Joost J F P
authors.initials: JJ
authors.lastname: Luiken
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Sayer
authors.forename: A Russell
authors.initials: AR
authors.lastname: Tupling
authors.forename: Adrian
authors.initials: A
authors.lastname: Chabowski
authors.forename: Graham P
authors.initials: GP
authors.lastname: Holloway
authors.forename: Arend
authors.initials: A
authors.lastname: Bonen
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001692:Biological Transport; D015153:Blotting, Western; D018955:CD36 Antigens / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D008112:Liver Glycogen / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008931:Mitochondria, Muscle / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D010084:Oxidation-Reduction; D010101:Oxygen Consumption; D010805:Physical Conditioning, Animal / Q000502:physiology*; D012508:Sarcolemma / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
chemical_list: D018955:CD36 Antigens; D005227:Fatty Acids; D008112:Liver Glycogen; D014280:Triglycerides; D005947:Glucose