Abstract 13833: FYCO1 Deficiency Blunts Cardiac Autophagy in vivo
Autophagy is a degradation pathway for recycling of intracellular components. Under resting conditions autophagy seems to be essential on a basal level. In contrast, upon stress conditions such as pressure overload autophagic flux in the heart is stimulated. Recently, we showed that FYCO1, a protein that is highly enriched in cardiac muscle and interacts with LC3, can induce autophagy in cardiomyocytes in vitro. In order to study the function of FYCO1 in vivo, we now generated a constitutive knockout mouse model. FYCO1 knockout (KO) mice developed normal until adulthood. As a knockdown of FYCO1 resulted in blunted autophagy after glucose deprivation in cardiomyocytes, we first subjected FYCO1 KO mice to 48 h of starvation. Interestingly, starved FYCO1 KO mice showed a significantly reduced fractional shortening by 12% (p<0.01, n=5) compared to wildtype (WT) littermates (n=5). Moreover, starvation of WT mice resulted in a 1.8 ± 0.2-fold increased level of LC3-II (p<0.01), a conjugated form of LC3 that correlates with the number of autophagosomes, compared to animals that received food. In contrast, the levels of LC3-II did not differ in KO mice due to starvation, consistent with inhibition of autophagy in the absence of FYCO1. Of note, a real time PCR array of autophagy-related genes revealed that gene regulation was not affected by FYCO1 deficiency in response to starvation. Since we had observed a reduction of FYCO1 expression by 44% (p=0.001) after transverse aortic constriction (TAC), we subjected FYCO1 KO mice to TAC. After 1 week of severe TAC, WT mice (n=7) displayed mild cardiac dysfunction with reduction of fractional shortening by 12% compared to WT sham operated mice (n=6). In FYCO1 KO mice we detected a reduction by 22% (p<0.05 compared WT TAC, n=10). Cardiac hypertrophy was not affected. TAC was associated with a 1.4 ± 0.1-fold increased level of LC3-II (p<0.05) in WT mice, while FYCO1 deficiency again blunted the level of LC3-II after TAC (0.8 ± 0.1-fold, p=n.s. compared to WT sham). In summary, we show that FYCO1 deficiency results in inhibition of autophagy in vivo. Moreover, the exacerbation of contractile dysfunction in response to starvation and pressure overload implies that FYCO1-mediated autophagy is required for proper adaptation to cardiac stress.
- © 2012 by American Heart Association, Inc.