Authors: Jared M McLendon, Xiaoming Zhang, Colleen S Stein, Nathan H Witmer, Gabrielle M Abouassaly, Ryan L Boudreau
Published: 2019-10-16
DOI: 10.1161/res.125.suppl_1.630
Source: Full article
Prior reports show that impaired cardiac function is associated with, if not caused by, Ubiquitin-Proteasome-System (UPS) dysfunction. Rodent loss-of-function studies for proteins involved in protein folding/ER stress responses, ubiquitin ligation, and proteasomal degradation are frequently associated with accumulation of misfolded/ubiquitinated proteins, decreased proteasomal activities, worse outcomes to cardiac stress, and premature death. By contrast, gain of function models that improve protein folding/trafficking or activate the proteasome prevent these molecular phenotypes and improve cardiac function. We have recently found an exception to this association while characterizing beta-taxilin (TXLNB), an understudied muscle- and heart-enriched protein with unknown function. In cardiomyocytes, TXLNB overexpression decreased ubiquitinated proteins and increased proteasome activity, whereas knockdown promotes proteasomal insufficiency. Similarly, hearts from TXLNB knockout (TXLNB-KO) mice show increased ubiquitinated proteins (>2-fold, n=8, p=.007) and decreased 26SB5 proteasome activity (~40%, n=8, p=.025), starting by 12 weeks of age and persisting through life. Despite robust cardiac proteasomal insufficiency, TXLNB-KO mice surprisingly exhibit normal cardiac function [echo/ekg measures done in several independent cohorts (n>7 per sex/genotype) up to ~24 months of age]. In addition, these mice do not show worse responses to mild pressure-overload induced by thoracic aortic constriction (n>13 per sex/genotype). While their cardiac function is normal, TXLNB-KO males do display slight reductions in heart growth with age (10 months, p=.023, n=7; 18 months, p=.07, n=11-17; 24 months, p=.026, n=3-4), suggesting that TXLNB function may interface with hypertrophic signaling. Together, our findings indicate that TXLNB serves to bolster cardiac UPS, and more importantly, that