title: IL-15 is required for postexercise induction of the pro-oxidative mediators PPARδ and SIRT1 in male mice.
abstract: Physical exercise induces transient upregulation of the pro-oxidative mediators peroxisome proliferator-activated receptor-δ (PPARδ), silent information regulator of transcription (sirtuin)-1 (SIRT1), PPARγ coactivator 1α (PGC-1α), and PGC-1β in skeletal muscle. To determine the role of the cytokine IL-15 in acute postexercise induction of these molecules, expression of these factors after a bout of exhaustive treadmill running was examined in the gastrocnemius muscle of untrained control and IL-15-knockout (KO) mice. Circulating IL-15 levels increased transiently in control mice after exercise. Control mice, but not IL-15-KO mice, upregulated muscle PPARδ and SIRT1 protein after exercise, accompanied by a complex pattern of mRNA expression for these factors. However, in exhaustive exercise, control mice ran significantly longer than IL-15-KO mice. Therefore, in a second experiment, mice were limited to a 20-minute run, after which a similar pattern of induction of muscle PPARδ and SIRT1 protein by control mice only was observed. In a separate experiment, IL-15-KO mice injected systemically with recombinant IL-15 upregulated muscle PPARδ and SIRT1 mRNA within 30 minutes and also exhibited increased muscle PPARδ protein levels by 3 hours. After exercise, both control and IL-15-KO mice downregulated IL-15 receptor-α (IL-15Rα) mRNA, whereas IL-15Rα-deficient mice exhibited constitutively elevated circulating IL-15 levels. These observations indicate IL-15 release after exercise is necessary for induction of PPARδ and SIRT1 at the protein level in muscle tissue and suggest that exercise releases IL-15 normally sequestered by the IL-15Rα in the resting state. These findings could be used to develop an IL-15-based strategy to induce many of the metabolic benefits of physical exercise.
authors.affiliation: Geriatric Research, Education, and Clinical Center (L.S.Q., B.G.A.) and Research Service (L.S.Q., J.D.C., T.W.-H.), VA Puget Sound Health Care System, and Seattle Institute for Biomedical and Clinical Research (L.S.Q., J.D.C.), Seattle, Washington 98108; Division of Gerontology and Geriatric Medicine (L.S.Q., B.G.A.), Department of Medicine, University of Washington, Seattle, Washington 98195; and Department of Kinesiology (T.J.M.), California State University Stanislaus, Turlock, California 95382.
authors.forename: Lebris S
authors.initials: LS
authors.lastname: Quinn
authors.forename: Barbara G
authors.initials: BG
authors.lastname: Anderson
authors.forename: Jennifer D
authors.initials: JD
authors.lastname: Conner
authors.forename: Tami
authors.initials: T
authors.lastname: Wolden-Hanson
authors.forename: Taylor J
authors.initials: TJ
authors.lastname: Marcell
mesh_terms: D000818:Animals; D001823:Body Composition; D005786:Gene Expression Regulation; D019409:Interleukin-15 / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000502:physiology*; D010100:Oxygen / Q000502:physiology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010805:Physical Conditioning, Animal; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D056564:Sirtuin 1 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D019409:Interleukin-15; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C091778:Ppard protein, mouse; C485290:Ppargc1a protein, mouse; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D010100:Oxygen