Abstract 316: Enhanced Cardiac Proteasome Function in the Naked Mole-rat, the Longest-lived Rodent

Abstract

The ubiquitin-proteasome system (UPS) is responsible for the recycling of misfolded proteins. Dysfunction of the UPS has been implicated in the pathophysiology of multiple heart disorders, including heart failure and reperfusion injury, but the basic science of cardiac UPS function remains unclear. An attractive mode of inquiry into the cardiac proteasome is the long-lived naked mole rat (NMR), which maintains intact cardiac reserve and diastolic function exceptionally late into its lifespan; equivalent to a 90 year old human with a 30 year old’s heart. In this study, we investigated whether the long-lived and healthful NMR had upregulated aspects of UPS function in comparison to the short-lived well-characterized mouse. NMR hearts have more than twofold (p<0.001) greater proteasome-mediated chymotrypsin-like activity than mouse hearts. NMR hearts also have significantly greater levels of proteasome subunits than mice, including α7 and Rpt5, suggesting that the greater numbers of proteasomes could contribute to the high chymotrypsin-like activity, alternatively, the naked mole-rat heart may also have more immunoproteasomes which are more efficient. The UPS is energy-dependent, with its activity significantly influenced by available ATP. Interestingly, basal ATP levels were 40 to 50 fold higher in NMR hearts than in those of mice. This is consistent with the much larger pools of mitochondria observed in the NMR heart than in the mouse heart. Considering that both high and low ATP levels are associated with a decline in proteasome activity, we next asked whether the remarkably high basal ATP levels of the NMR heart caused a qualitative difference in UPS function between NMRs and mice. Levels of ubiquitinated protein were significantly lower in the NMR heart than in the mouse heart, suggesting that the NMR cardiac UPS system is more effective at destroying ubiquitin-tagged damaged proteins than that of the mouse, and that the NMR heart’s elevated ATP levels may play a physiological role in maintaining this enhanced UPS functionality. Overall these data suggest a high basal level of proteasome activity in the NMR heart that may be of paramount importance in this animal’s ability to withstand and/or prevent age-related cardiovascular functional declines.