Metabolic dysfunction consistent with premature aging results from deletion of pim kinases

Shabana Din, Mathias H. Konstandin, Bevan Johnson, Jacqueline Emathinger, Mirko Völkers, Haruhiro Toko, Brett Collins, Lucy Ormachea, Kaitlen Samse, Dieter A. Kubli, Andrea De La Torre, Andrew Kraft, Asa B. Gustafsson, Daniel P. Kelly, Mark A. Sussman

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

RATIONALE:: 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. METHODS AND 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.

Original languageEnglish (US)
Pages (from-to)376-387
Number of pages12
JournalCirculation Research
Volume115
Issue number3
DOIs
StatePublished - Jul 18 2014
Externally publishedYes

Fingerprint

Premature Aging
Knockout Mice
Organelle Biogenesis
Phenotype
Proto-Oncogene Proteins c-pim-1
Proto-Oncogene Proteins c-myc
AMP-Activated Protein Kinases
Cardiac Myocytes
Transcriptional Activation
Mitochondria
Protein Isoforms
Fatty Acids
Heart Failure
Adenosine Triphosphate
proto-oncogene proteins pim
Gene Expression

Keywords

  • aging
  • hypertrophy
  • metabolism
  • proto-oncogene proteins pim

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Din, S., Konstandin, M. H., Johnson, B., Emathinger, J., Völkers, M., Toko, H., ... Sussman, M. A. (2014). Metabolic dysfunction consistent with premature aging results from deletion of pim kinases. Circulation Research, 115(3), 376-387. https://doi.org/10.1161/CIRCRESAHA.115.304441

Metabolic dysfunction consistent with premature aging results from deletion of pim kinases. / Din, Shabana; Konstandin, Mathias H.; Johnson, Bevan; Emathinger, Jacqueline; Völkers, Mirko; Toko, Haruhiro; Collins, Brett; Ormachea, Lucy; Samse, Kaitlen; Kubli, Dieter A.; De La Torre, Andrea; Kraft, Andrew; Gustafsson, Asa B.; Kelly, Daniel P.; Sussman, Mark A.

In: Circulation Research, Vol. 115, No. 3, 18.07.2014, p. 376-387.

Research output: Contribution to journalArticle

Din, S, Konstandin, MH, Johnson, B, Emathinger, J, Völkers, M, Toko, H, Collins, B, Ormachea, L, Samse, K, Kubli, DA, De La Torre, A, Kraft, A, Gustafsson, AB, Kelly, DP & Sussman, MA 2014, 'Metabolic dysfunction consistent with premature aging results from deletion of pim kinases', Circulation Research, vol. 115, no. 3, pp. 376-387. https://doi.org/10.1161/CIRCRESAHA.115.304441
Din S, Konstandin MH, Johnson B, Emathinger J, Völkers M, Toko H et al. Metabolic dysfunction consistent with premature aging results from deletion of pim kinases. Circulation Research. 2014 Jul 18;115(3):376-387. https://doi.org/10.1161/CIRCRESAHA.115.304441
Din, Shabana ; Konstandin, Mathias H. ; Johnson, Bevan ; Emathinger, Jacqueline ; Völkers, Mirko ; Toko, Haruhiro ; Collins, Brett ; Ormachea, Lucy ; Samse, Kaitlen ; Kubli, Dieter A. ; De La Torre, Andrea ; Kraft, Andrew ; Gustafsson, Asa B. ; Kelly, Daniel P. ; Sussman, Mark A. / Metabolic dysfunction consistent with premature aging results from deletion of pim kinases. In: Circulation Research. 2014 ; Vol. 115, No. 3. pp. 376-387.
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abstract = "RATIONALE:: 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. METHODS AND 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.",
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AU - Toko, Haruhiro

AU - Collins, Brett

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AU - Samse, Kaitlen

AU - Kubli, Dieter A.

AU - De La Torre, Andrea

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AU - Gustafsson, Asa B.

AU - Kelly, Daniel P.

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N2 - RATIONALE:: 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. METHODS AND 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.

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