Back to Search
Start Over
Metabolic dysfunction consistent with premature aging results from deletion of Pim kinases.
- Source :
-
Circulation research [Circ Res] 2014 Jul 18; Vol. 115 (3), pp. 376-87. Date of Electronic Publication: 2014 Jun 10. - Publication Year :
- 2014
-
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.<br />Objective: To demonstrate that myocardial senescence is promoted by loss of Pim leading to premature aging and aberrant mitochondrial function.<br />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.<br />Conclusions: Pim kinases prevent premature cardiac aging and maintain a healthy pool of functional mitochondria leading to efficient cellular energetics.<br /> (© 2014 American Heart Association, Inc.)
- Subjects :
- Aging, Premature genetics
Aging, Premature pathology
Animals
Cardiomegaly pathology
Cell Line, Transformed
Cell Respiration genetics
Cellular Senescence genetics
Fibroblasts cytology
Fibroblasts metabolism
Humans
Mice
Mice, Knockout
Myocytes, Cardiac cytology
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
Proto-Oncogene Mas
Proto-Oncogene Proteins c-myc genetics
Proto-Oncogene Proteins c-myc metabolism
Proto-Oncogene Proteins c-pim-1 metabolism
RNA, Small Interfering genetics
Rats
Telomere metabolism
Transcription Factors genetics
Transcription Factors metabolism
Aging, Premature metabolism
Cardiomegaly metabolism
Mitochondria, Heart metabolism
Myocytes, Cardiac metabolism
Proto-Oncogene Proteins c-pim-1 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4571
- Volume :
- 115
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Circulation research
- Publication Type :
- Academic Journal
- Accession number :
- 24916111
- Full Text :
- https://doi.org/10.1161/CIRCRESAHA.115.304441