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Deployed service members and first responders are exposed to environments containing high levels of air pollution and psychological distress. Thus, we sought to investigate the interaction of these factors and whether the combination of PM and stress exposures exacerbate cardiac and lung dysfunction in a mouse model. Male C57BL/6 mice were exposed to filtered air (FA) or PM (≤2.5 μm) at concentrations of 137.7 ± 70.76 μg/m 3 (daily mean ± standard deviation) for five days/week for three weeks. A subset of each group was stressed via exposure to a retired male aggressor for two hours/day, 3-5 nights/week (FA-stress and PM-stress groups). Echocardiography revealed no changes in left ventricle (LV) systolic or diastolic indices, but a significant reduction in right ventricle (RV) stroke volume and cardiac output in the PM, FA-stress and PM-stress groups compared to the FA group (P

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.

Aging is associated with metabolic dysfunction and metabolic dysfunction accelerates the course of aging. This is well illustrated by aging-like phenotypes displayed in the Polymerase Gamma mutant mouse. Here, a key residue of the mitochondrial DNA polymerase is mutated (D257A) which hinders proof reading capacity, resulting in mitochondrial DNA mutation and instability. Given known cardiac phenotypes in the POLG mutant mouse, we sought to characterize the course of cardiac dysfunction in the POLG mutant to guide future intervention studies. Including both male and female animals allowed interrogation of sex-specific responses to severe metabolic dysfunction. We also conducted RNA-seq analysis on cardiac right ventricles to broadly identify mechanisms engaged by severe metabolic dysfunction that are associated with RV pathology. Several interesting sex differences were noted. Specifically, female POLG mutants died earlier than male POLG mutants and LV chamber diameters were impacted earlier in females than males. Moreover, male POLG mutants showed LV wall thinning while female POLG mutant LV walls were thicker. Both males and females displayed significant RV hypertrophy. Finally, RNA-seq analysis of the RV tissue indicated that POLG mutation significantly impacted canonical pathways associated with inflammation, fibrosis, and heart failure. Comparison of this RNA-seq dataset with other publically available datasets highlight 1) strong conservation among downregulated genes in models of accelerated cardiac aging, 2) the potential involvement of the mitochondrial unfolded protein response in the POLG mutant, and 3) the ability of zinc dependent HDAC inhibition to rescue the expression of genes downregulated in accelerated cardiac aging.