title: Skeletal muscle uncoupling-induced longevity in mice is linked to increased substrate metabolism and induction of the endogenous antioxidant defense system.
abstract: Ectopic expression of uncoupling protein 1 (UCP1) in skeletal muscle (SM) mitochondria increases lifespan considerably in high-fat diet-fed UCP1 Tg mice compared with wild types (WT). To clarify the underlying mechanisms, we investigated substrate metabolism as well as oxidative stress damage and antioxidant defense in SM of low-fat- and high-fat-fed mice. Tg mice showed an increased protein expression of phosphorylated AMP-activated protein kinase, markers of lipid turnover (p-ACC, FAT/CD36), and an increased SM ex vivo fatty acid oxidation. Surprisingly, UCP1 Tg mice showed elevated lipid peroxidative protein modifications with no changes in glycoxidation or direct protein oxidation. This was paralleled by an induction of catalase and superoxide dismutase activity, an increased redox signaling (MAPK signaling pathway), and increased expression of stress-protective heat shock protein 25. We conclude that increased skeletal muscle mitochondrial uncoupling in vivo does not reduce the oxidative stress status in the muscle cell. Moreover, it increases lipid metabolism and reactive lipid-derived carbonyls. This stress induction in turn increases the endogenous antioxidant defense system and redox signaling. Altogether, our data argue for an adaptive role of reactive species as essential signaling molecules for health and longevity.
authors.affiliation: German Institute of Human Nutrition, Potsdam-Rehbruecke, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Keipert
authors.forename: M
authors.initials: M
authors.lastname: Ost
authors.forename: A
authors.initials: A
authors.lastname: Chadt
authors.forename: A
authors.initials: A
authors.lastname: Voigt
authors.forename: V
authors.initials: V
authors.lastname: Ayala
authors.forename: M
authors.initials: M
authors.lastname: Portero-Otin
authors.forename: R
authors.initials: R
authors.lastname: Pamplona
authors.forename: H
authors.initials: H
authors.lastname: Al-Hasani
authors.forename: S
authors.initials: S
authors.lastname: Klaus
mesh_terms: D000154:Aconitate Hydratase / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D015415:Biomarkers; D001823:Body Composition / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D002374:Catalase / Q000097:blood; D004041:Dietary Fats / Q000009:adverse effects; D005227:Fatty Acids / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D008136:Longevity / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009124:Muscle Proteins / Q000096:biosynthesis / Q000235:genetics; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000502:physiology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D060888:Real-Time Polymerase Chain Reaction; D013482:Superoxide Dismutase / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
chemical_list: D000975:Antioxidants; D015415:Biomarkers; D004041:Dietary Fats; D005227:Fatty Acids; D009124:Muscle Proteins; D014280:Triglycerides; D002374:Catalase; D013482:Superoxide Dismutase; D020928:Mitogen-Activated Protein Kinases; D000154:Aconitate Hydratase