title: Activation of AMPKα2 is not crucial for mitochondrial uncoupling-induced metabolic effects but required to maintain skeletal muscle integrity.
abstract: Transgenic (UCP1-TG) mice with ectopic expression of UCP1 in skeletal muscle (SM) show a phenotype of increased energy expenditure, improved glucose tolerance and increase substrate metabolism in SM. To investigate the potential role of skeletal muscle AMPKα2 activation in the metabolic phenotype of UCP1-TG mice we generated double transgenic (DTG) mice, by crossing of UCP1-TG mice with DN-AMPKα2 mice overexpressing a dominant negative α2 subunit of AMPK in SM which resulted in an impaired AMPKα2 activity by 90±9% in SM of DTG mice. Biometric analysis of young male mice showed decreased body weight, lean and fat mass for both UCP1-TG and DTG compared to WT and DN-AMPKα2 mice. Energy intake and weight-specific total energy expenditure were increased, both in UCP1-TG and DTG mice. Moreover, glucose tolerance, insulin sensitivity and fatty acid oxidation were not altered in DTG compared to UCP1-TG. Also uncoupling induced induction and secretion of fibroblast growth factor 21 (FGF21) from SM was preserved in DTG mice. However, voluntary physical cage activity as well as ad libitum running wheel access during night uncovered a severe activity intolerance of DTG mice. Histological analysis showed a progressive degenerative morphology in SM of DTG mice which was not observed in SM of UCP1-TG mice. Moreover, ATP-depletion related cellular stress response via heat shock protein 70 was highly induced, whereas capillarization regulator VEGF was suppressed in DTG muscle. In addition, AMPKα2-mediated induction of mitophagy regulator ULK1 was suppressed in DTG mice, as well as mitochondrial respiratory capacity and content. In conclusion, we demonstrate that AMPKα2 is dispensable for SM mitochondrial uncoupling induced metabolic effects on whole body energy balance, glucose homeostasis and insulin sensitivity. But strikingly, activation of AMPKα2 seems crucial for maintaining SM function, integrity and the ability to compensate chronic metabolic stress induced by SM mitochondrial uncoupling.
authors.affiliation: German Institute of Human Nutrition (DIfE) Potsdam-Rehbruecke, Nuthetal, Germany.
authors.forename: Mario
authors.initials: M
authors.lastname: Ost
authors.affiliation: German Institute of Human Nutrition (DIfE) Potsdam-Rehbruecke, Nuthetal, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Werner
authors.affiliation: German Institute of Human Nutrition (DIfE) Potsdam-Rehbruecke, Nuthetal, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Dokas
authors.affiliation: German Institute of Human Nutrition (DIfE) Potsdam-Rehbruecke, Nuthetal, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Klaus
authors.affiliation: German Institute of Human Nutrition (DIfE) Potsdam-Rehbruecke, Nuthetal, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Voigt
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D001835:Body Weight; D018955:CD36 Antigens / Q000378:metabolism; D003433:Crosses, Genetic; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D007473:Ion Channels / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics; D018482:Muscle, Skeletal / Q000502:physiology*; D010641:Phenotype; D010766:Phosphorylation; D014475:Uncoupling Agents / Q000378:metabolism; D000071256:Uncoupling Protein 1
chemical_list: D018955:CD36 Antigens; D005227:Fatty Acids; D007473:Ion Channels; D024101:Mitochondrial Proteins; C000604371:UCP1 protein, human; C000604372:Ucp1 protein, mouse; D014475:Uncoupling Agents; D000071256:Uncoupling Protein 1; C534978:Prkaa2 protein, mouse; D055372:AMP-Activated Protein Kinases; D005947:Glucose
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