期刊
LIFE SCIENCES
卷 298, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.lfs.2022.120469
关键词
Right ventricle; Polymerase Gamma; Sex-specific; RNA-Seq
资金
- NIH [AG056848, AHA 857280]
- DHLRI institutional funds
Metabolic dysfunction plays a central role in aging biology. This study investigates the cardiac dysfunction in a mutant mouse model with Polymerase Gamma (POLG) mutation, which leads to accelerated aging processes. The results show interesting sex differences in cardiac phenotypes and gene expression patterns associated with inflammation, fibrosis, and heart failure. These findings provide insights into the molecular mechanisms of cardiac dysfunction and potential therapeutic targets.
Aims: Metabolic function/dysfunction is central to aging biology. This is well illustrated by the Polymerase Gamma (POLG) mutant mouse where a key residue of the mitochondrial DNA polymerase is mutated (D257A), causing loss of mitochondrial DNA stability and dramatically accelerated aging processes. Given known cardiac phenotypes in the POLG mutant, we sought to characterize the course of cardiac dysfunction in the POLG mutant to guide future intervention studies.Materials and methods: Cardiac echocardiography and terminal hemodynamic analyses were used to define the course of dysfunction in the right and left cardiac ventricles in the POLG mutant. We also conducted RNA-seq analysis on cardiac right ventricles to identify mechanisms engaged by severe metabolic dysfunction and compared this analysis to several publically available datasets.Key findings: Interesting sex differences were noted as female POLG mutants died earlier than male POLG mutants and LV chamber diameters were impacted earlier in females than males. Moreover, male mutants showed LV wall thinning while female mutant LV walls were thicker. Both males and females displayed significant RV hypertrophy. POLG mutants displayed a gene expression pattern associated with inflammation, fibrosis, and heart failure. Finally, comparative omics analyses of publically available data provide additional mechanistic and therapeutic insights.Significance: Aging-associated cardiac dysfunction is a growing clinical problem. This work uncovers sex-specific cardiac responses to severe metabolic dysfunction that are reminiscent of patterns seen in human heart failure and provides insights to the molecular mechanisms engaged downstream of severe metabolic dysfunction that warrant further investigation.
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