The TGAC8 Mouse, the mouse that roars

National Institute On Aging

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Abstract

1. We performed traditional bioinformatic analysis of RNASEQ data to determine the differential expression of transcripts changing between genotypes in young and old LVS lysate samples of TgAC8 and WT mice.In order to determine to what extent transcripts differently changed with age we analyzed the 17906 transcripts in a two-way ANOVA to determine which genes changed only with Age but not genotype, which genes changed only by Genotype but not by age, and which genes had Age-Genotype interaction. Out of 17906 transcripts 8921 transcripts did not change with age or genotype and didn’t have A:G interaction. 4782 differed by Age; 1704 differed by genotype; 1177 differed by age and genotype by the same extent and 3676 transcripts changed with age upon genotype. 2. Although the LV cardiac myocyte size increased with age in TgAC8 due to an increase in a subpopulation of LV myocytes, the LV muscle density became reduced due to an increase in the matrix which is due in large part to an increase in collagen. There was a marked age-associated increase in both myocyte and non-myocyte apoptosis in TgAC8 vs. WT. 3. Changes in cardiac structure and function that occurred with aging were more marked in the TgAC8 than WT. LVW thickness IVSd, PWd both increased with age in both genotypes. EDV increased with age in both genotypes but to a greater extent in TgAC8 than in WT. LVM, calculated from EDV and LV wall thickness, increased with age in both genotypes but to a greater extent in TgAC8 than WT. With respect to LV function, there was a marked inability of the LV of TgAC8 to shorten during systole compared to WT, resulting in a markedly age-association reduction in EF in the former vs. the later. The HR became reduced with age to a similar extent in both genotypes, but remained 15 % higher in the TgAC8 at the older ages compared to WT. In the context of an increase LVEDV and a reduced HR, Stroke volume increased with age in both groups. As a result of the greater HR in old TGAC8 than in WT, average CO remained approximately 20 % higher in TgAC8 vs WT. 4. We assessed protein quality control (PQC) mechanisms: ubiquitin proteasome system (UPS), autophagic flux via macroautophagy, and mitophagy in left ventricles (LVs) of TGAC8 and wild type littermates (WT) at 3-4 months and at 17-21 months of age. In advanced age, the PQC mechanisms were overwhelmed by proteotoxic stress, manifested in insufficient proteasome activity and an unbalanced autophagic flux (accelerated for markers such as LC3A in the context of a slower overall flux), leading to an increase in the accumulation of protein aggregates (increased ratio of insoluble/soluble protein fractions). Although both canonical (PARKIN, p62S403 and p62S349 receptors) and non-canonical (FKBP8 receptor) mitophagy signaling were upregulated in advanced age in TGAC8, mitophagy was markedly impaired and mitochondrial dysfunction increased.