title: Subsarcolemmal and intermyofibrillar mitochondria play distinct roles in regulating skeletal muscle fatty acid metabolism.
abstract: Skeletal muscle contains two populations of mitochondria that appear to be differentially affected by disease and exercise training. It remains unclear how these mitochondrial subpopulations contribute to fiber type-related and/or training-induced changes in fatty acid oxidation and regulation of carnitine palmitoyltransferase-1beta (CPT1beta), the enzyme that controls mitochondrial fatty acid uptake in skeletal muscle. To this end, we found that fatty acid oxidation rates were 8.9-fold higher in subsarcolemmal mitochondria (SS) and 5.3-fold higher in intermyofibrillar mitochondria (IMF) that were isolated from red gastrocnemius (RG) compared with white gastrocnemius (WG) muscle, respectively. Malonyl-CoA (10 muM), a potent inhibitor of CPT1beta, completely abolished fatty acid oxidation in SS and IMF mitochondria from WG, whereas oxidation rates in the corresponding fractions from RG were inhibited only 89% and 60%, respectively. Endurance training also elicited mitochondrial adaptations that resulted in enhanced fatty acid oxidation capacity. Ten weeks of treadmill running differentially increased palmitate oxidation rates 100% and 46% in SS and IMF mitochondria, respectively. In SS mitochondria, elevated fatty acid oxidation rates were accompanied by a 48% increase in citrate synthase activity but no change in CPT1 activity. Nonlinear regression analyses of mitochondrial fatty acid oxidation rates in the presence of 0-100 muM malonyl-CoA indicated that IC(50) values were neither dependent on mitochondrial subpopulation nor affected by exercise training. However, in IMF mitochondria, training reduced the Hill coefficient (P < 0.05), suggesting altered CPT1beta kinetics. These results demonstrate that endurance exercise provokes subpopulation-specific changes in mitochondrial function that are characterized by enhanced fatty acid oxidation and modified CPT1beta-malonyl-CoA dynamics.
authors.affiliation: Department of Physiology, Brody School of Medicine, College of Health and Human Performance, East Carolina University, Greenville, North Carolina, USA.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Koves
authors.forename: Robert C
authors.initials: RC
authors.lastname: Noland
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Bates
authors.forename: Sarah T
authors.initials: ST
authors.lastname: Henes
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Muoio
authors.forename: Ronald N
authors.initials: RN
authors.lastname: Cortright
mesh_terms: D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000302:isolation & purification / Q000378:metabolism*; D002950:Citrate (si)-Synthase / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D008297:Male; D008316:Malonyl Coenzyme A / Q000494:pharmacology; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009210:Myofibrils / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D010168:Palmitates / Q000378:metabolism*; D010807:Physical Endurance / Q000502:physiology; D005082:Physical Exertion / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D010168:Palmitates; D008316:Malonyl Coenzyme A; D002334:Carnitine O-Palmitoyltransferase; D002950:Citrate (si)-Synthase