Cold tolerance of UCP1-ablated mice: a skeletal muscle mitochondria switch toward lipid oxidation with marked UCP3 up-regulation not associated with increased basal, fatty acid- or ROS-induced uncoupling or enhanced GDP effects.
Mice lacking the thermogenic mitochondrial membrane protein UCP1 (uncoupling protein 1)--and thus all heat production from brown adipose tissue--can still adapt to a cold environment (4 degrees C) if successively transferred to the cold. The mechanism behind this adaptation has not been clarified. To examine possible adaptive processes in the skeletal muscle, we isolated mitochondria from the hind limb muscles of cold-acclimated wild-type and UCP1(-/-) mice and examined their bioenergetic chracteristics. We observed a switch in metabolism, from carbohydrate towards lipid catabolism, and an increased total mitochondrial complement, with an increased total ATP production capacity. The UCP1(-/-) muscle mitochondria did not display a changed state-4 respiration rate (no uncoupling) and were less sensitive to the uncoupling effect of fatty acids than the wild-type mitochondria. The content of UCP3 was increased 3-4 fold, but despite this, endogenous superoxide could not invoke a higher proton leak, and the small inhibitory effect of GDP was unaltered, indicating that it was not mediated by UCP3. Double mutant mice (UCP1(-/-) plus superoxide dismutase 2-overexpression) were not more cold sensitive than UCP1(-/-), bringing into question an involvement of reactive oxygen species (ROS) in activation of any alternative thermogenic mechanism. We conclude that there is no evidence for an involvement of UCP3 in basal, fatty-acid- or superoxide-stimulated oxygen consumption or in GDP sensitivity. The adaptations observed did not imply any direct alternative process for nonshivering thermogenesis but the adaptations observed would be congruent with adaptation to chronically enhanced muscle activity caused by incessant shivering in these mice.
The Wenner-Gren Institute, Stockholm University, SE-106 91 Stockholm, Sweden.
Irina G
IG
Shabalina
Joris
J
Hoeks
Tatiana V
TV
Kramarova
Patrick
P
Schrauwen
Barbara
B
Cannon
Jan
J
Nedergaard
D000064:Acclimatization / Q000235:genetics / Q000502:physiology*; D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D003080:Cold Temperature; D004734:Energy Metabolism; D005227:Fatty Acids / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D006153:Guanosine Diphosphate / Q000494:pharmacology; D066298:In Vitro Techniques; D007473:Ion Channels / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D015227:Lipid Peroxidation; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism; D018384:Oxidative Stress; D010101:Oxygen Consumption; D017382:Reactive Oxygen Species / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D022722:Thermogenesis / Q000235:genetics / Q000502:physiology; D000071256:Uncoupling Protein 1; D000071247:Uncoupling Protein 3; D015854:Up-Regulation
D005227:Fatty Acids; D007473:Ion Channels; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; C000604372:Ucp1 protein, mouse; C000604393:Ucp3 protein, mouse; D000071256:Uncoupling Protein 1; D000071247:Uncoupling Protein 3; D013481:Superoxides; D006153:Guanosine Diphosphate; D000255:Adenosine Triphosphate