miR-199-sponge transgenic mice develop physiological cardiac hypertrophy

Aims Overexpression of either member of the miR-199 family, miR-199a-5p, or miR-199b-5p (hereinafter referred to as miR-199a or miR-199b) promotes pathological cardiac hypertrophy, but little is known about the role of endogenous miR-199 in cardiac development and disease. Our study aimed to determine the physiological function of the endogenous miR-199 family in cardiac homeostasis maintenance. Methods and results We generated a sponge transgenic mouse model with a specific disruption of miR-199 in the heart. To our surprise, we found that knockdown of endogenous miR-199 caused physiological cardiac hypertrophy characterized by an increased heart weight and cardiomyocyte size, but with normal cardiac morphology and function. Furthermore, we also identified PGC1 alpha as the target gene of the miR-199 family, and PGC1 alpha was also increased in sponge transgenic mice. Conclusion Inhibition of endogenous miR-199 led to physiological cardiac hypertrophy probably due to the up-regulation of PGC1 alpha, uncovering a surprising role for endogenous miR-199 in the maintenance of cardiac homeostasis.