title: Metabolic dysfunction consistent with premature aging results from deletion of Pim kinases.
abstract: BACKGROUND
  The senescent cardiac phenotype is accompanied by changes in mitochondrial function and biogenesis causing impairment in energy provision. The relationship between myocardial senescence and Pim kinases deserves attention because Pim-1 kinase is cardioprotective, in part, by preservation of mitochondrial integrity. Study of the pathological effects resulting from genetic deletion of all Pim kinase family members could provide important insight about cardiac mitochondrial biology and the aging phenotype.
  
  
  OBJECTIVE
  To demonstrate that myocardial senescence is promoted by loss of Pim leading to premature aging and aberrant mitochondrial function.
  
  
  RESULTS
  Cardiac myocyte senescence was evident at 3 months in Pim triple knockout mice, where all 3 isoforms of Pim kinase family members are genetically deleted. Cellular hypertrophic remodeling and fetal gene program activation were followed by heart failure at 6 months in Pim triple knockout mice. Metabolic dysfunction is an underlying cause of cardiac senescence and instigates a decline in cardiac function. Altered mitochondrial morphology is evident consequential to Pim deletion together with decreased ATP levels and increased phosphorylated AMP-activated protein kinase, exposing an energy deficiency in Pim triple knockout mice. Expression of the genes encoding master regulators of mitochondrial biogenesis, PPARγ (peroxisome proliferator-activated receptor gamma) coactivator-1 α and β, was diminished in Pim triple knockout hearts, as were downstream targets included in mitochondrial energy transduction, including fatty acid oxidation. Reversal of the dysregulated metabolic phenotype was observed by overexpressing c-Myc (Myc proto-oncogene protein), a downstream target of Pim kinases.
  
  
  CONCLUSIONS
  Pim kinases prevent premature cardiac aging and maintain a healthy pool of functional mitochondria leading to efficient cellular energetics.
authors.affiliation: From the Department of Biology, San Diego State Heart Institute, San Diego State University, CA (S.D., M.H.K., B.J., J.E., M.V., H.T., B.C., L.O., K.S., A.D.L.T., M.A.S.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla (D.A.K., A.B.G.); and Department of Medicine, Medical University of South Carolina Hollings Cancer Center, Charleston (A.S.K.), and Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Orlando, FL (D.P.K.).
authors.forename: Shabana
authors.initials: S
authors.lastname: Din
authors.affiliation: From the Department of Biology, San Diego State Heart Institute, San Diego State University, CA (S.D., M.H.K., B.J., J.E., M.V., H.T., B.C., L.O., K.S., A.D.L.T., M.A.S.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla (D.A.K., A.B.G.); and Department of Medicine, Medical University of South Carolina Hollings Cancer Center, Charleston (A.S.K.), and Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Orlando, FL (D.P.K.).
authors.forename: Mathias H
authors.initials: MH
authors.lastname: Konstandin
authors.affiliation: From the Department of Biology, San Diego State Heart Institute, San Diego State University, CA (S.D., M.H.K., B.J., J.E., M.V., H.T., B.C., L.O., K.S., A.D.L.T., M.A.S.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla (D.A.K., A.B.G.); and Department of Medicine, Medical University of South Carolina Hollings Cancer Center, Charleston (A.S.K.), and Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Orlando, FL (D.P.K.).
authors.forename: Bevan
authors.initials: B
authors.lastname: Johnson
authors.affiliation: From the Department of Biology, San Diego State Heart Institute, San Diego State University, CA (S.D., M.H.K., B.J., J.E., M.V., H.T., B.C., L.O., K.S., A.D.L.T., M.A.S.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla (D.A.K., A.B.G.); and Department of Medicine, Medical University of South Carolina Hollings Cancer Center, Charleston (A.S.K.), and Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Orlando, FL (D.P.K.).
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Emathinger
authors.affiliation: From the Department of Biology, San Diego State Heart Institute, San Diego State University, CA (S.D., M.H.K., B.J., J.E., M.V., H.T., B.C., L.O., K.S., A.D.L.T., M.A.S.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla (D.A.K., A.B.G.); and Department of Medicine, Medical University of South Carolina Hollings Cancer Center, Charleston (A.S.K.), and Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Orlando, FL (D.P.K.).
authors.forename: Mirko
authors.initials: M
authors.lastname: Völkers
authors.affiliation: From the Department of Biology, San Diego State Heart Institute, San Diego State University, CA (S.D., M.H.K., B.J., J.E., M.V., H.T., B.C., L.O., K.S., A.D.L.T., M.A.S.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla (D.A.K., A.B.G.); and Department of Medicine, Medical University of South Carolina Hollings Cancer Center, Charleston (A.S.K.), and Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Orlando, FL (D.P.K.).
authors.forename: Haruhiro
authors.initials: H
authors.lastname: Toko
authors.affiliation: From the Department of Biology, San Diego State Heart Institute, San Diego State University, CA (S.D., M.H.K., B.J., J.E., M.V., H.T., B.C., L.O., K.S., A.D.L.T., M.A.S.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla (D.A.K., A.B.G.); and Department of Medicine, Medical University of South Carolina Hollings Cancer Center, Charleston (A.S.K.), and Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Orlando, FL (D.P.K.).
authors.forename: Brett
authors.initials: B
authors.lastname: Collins
authors.affiliation: From the Department of Biology, San Diego State Heart Institute, San Diego State University, CA (S.D., M.H.K., B.J., J.E., M.V., H.T., B.C., L.O., K.S., A.D.L.T., M.A.S.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla (D.A.K., A.B.G.); and Department of Medicine, Medical University of South Carolina Hollings Cancer Center, Charleston (A.S.K.), and Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Orlando, FL (D.P.K.).
authors.forename: Lucy
authors.initials: L
authors.lastname: Ormachea
authors.affiliation: From the Department of Biology, San Diego State Heart Institute, San Diego State University, CA (S.D., M.H.K., B.J., J.E., M.V., H.T., B.C., L.O., K.S., A.D.L.T., M.A.S.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla (D.A.K., A.B.G.); and Department of Medicine, Medical University of South Carolina Hollings Cancer Center, Charleston (A.S.K.), and Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Orlando, FL (D.P.K.).
authors.forename: Kaitlen
authors.initials: K
authors.lastname: Samse
authors.affiliation: From the Department of Biology, San Diego State Heart Institute, San Diego State University, CA (S.D., M.H.K., B.J., J.E., M.V., H.T., B.C., L.O., K.S., A.D.L.T., M.A.S.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla (D.A.K., A.B.G.); and Department of Medicine, Medical University of South Carolina Hollings Cancer Center, Charleston (A.S.K.), and Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Orlando, FL (D.P.K.).
authors.forename: Dieter A
authors.initials: DA
authors.lastname: Kubli
authors.affiliation: From the Department of Biology, San Diego State Heart Institute, San Diego State University, CA (S.D., M.H.K., B.J., J.E., M.V., H.T., B.C., L.O., K.S., A.D.L.T., M.A.S.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla (D.A.K., A.B.G.); and Department of Medicine, Medical University of South Carolina Hollings Cancer Center, Charleston (A.S.K.), and Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Orlando, FL (D.P.K.).
authors.forename: Andrea
authors.initials: A
authors.lastname: De La Torre
authors.affiliation: From the Department of Biology, San Diego State Heart Institute, San Diego State University, CA (S.D., M.H.K., B.J., J.E., M.V., H.T., B.C., L.O., K.S., A.D.L.T., M.A.S.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla (D.A.K., A.B.G.); and Department of Medicine, Medical University of South Carolina Hollings Cancer Center, Charleston (A.S.K.), and Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Orlando, FL (D.P.K.).
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Kraft
authors.affiliation: From the Department of Biology, San Diego State Heart Institute, San Diego State University, CA (S.D., M.H.K., B.J., J.E., M.V., H.T., B.C., L.O., K.S., A.D.L.T., M.A.S.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla (D.A.K., A.B.G.); and Department of Medicine, Medical University of South Carolina Hollings Cancer Center, Charleston (A.S.K.), and Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Orlando, FL (D.P.K.).
authors.forename: Asa B
authors.initials: AB
authors.lastname: Gustafsson
authors.affiliation: From the Department of Biology, San Diego State Heart Institute, San Diego State University, CA (S.D., M.H.K., B.J., J.E., M.V., H.T., B.C., L.O., K.S., A.D.L.T., M.A.S.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla (D.A.K., A.B.G.); and Department of Medicine, Medical University of South Carolina Hollings Cancer Center, Charleston (A.S.K.), and Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Orlando, FL (D.P.K.).
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Kelly
authors.affiliation: From the Department of Biology, San Diego State Heart Institute, San Diego State University, CA (S.D., M.H.K., B.J., J.E., M.V., H.T., B.C., L.O., K.S., A.D.L.T., M.A.S.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla (D.A.K., A.B.G.); and Department of Medicine, Medical University of South Carolina Hollings Cancer Center, Charleston (A.S.K.), and Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Orlando, FL (D.P.K.). heartman4ever@icloud.com.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Sussman
mesh_terms: D019588:Aging, Premature / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology; D002461:Cell Line, Transformed; D019069:Cell Respiration / Q000235:genetics; D016922:Cellular Senescence / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D051573:Proto-Oncogene Proteins c-pim-1 / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D016615:Telomere / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C000715470:MAS1 protein, human; C489428:Myc protein, mouse; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D014157:Transcription Factors; C496636:Pim1 protein, mouse; C496637:Pim1 protein, rat; D051573:Proto-Oncogene Proteins c-pim-1
keywords: aging; hypertrophy; metabolism; proto-oncogene proteins pim