E3 ubiquitin ligase RBX1 inhibits glutamine metabolism and attenuates cardiomyocyte hypertrophy.

Cardiac hypertrophy is an independent risk factor for cardiovascular disease, and with the progress of research, metabolic reprogramming has been recognized as a key mechanism in the development of several cardiac diseases. Recently, increased glutamine metabolism has been found to be strongly associated with cardiomyocyte hypertrophy, but the exact mechanism has not been elucidated. Our investigation confirmed that inhibition of glutamine metabolism reversed cardiomyocyte hypertrophy and that this metabolic alteration was associated with c-Myc. Meanwhile, the role of ubiquitination modification in maintaining protein homeostasis and cardiac function has been a hot research topic, we found that the E3 ubiquitin ligase RBX1 was significantly decreased in cardiomyocyte hypertrophy model and was accompanied by an increase in c-Myc mediated glutamine metabolism. However, RBX1 did not bind directly to c-Myc. Subsequently, we found that RBX1 interacts with the transcription factor FoxO1 by prediction, and the latter showed elevated protein expression without significant changes in mRNA levels in the cardiac hypertrophy model, suggesting a post-translational modification process. We found that RBX1 plays a protective role in cardiomyocyte hypertrophy by degrading FoxO1 through ubiquitination and thereby affecting c-Myc mediated glutamine metabolism. Collectively, these findings suggest that strategies based on inhibition of the RBX1/FoxO1 axis may hold promise for the treatment of cardiomyocyte hypertrophy.