RATIONALE: Myostatin is a major negative regulator of skeletal muscle mass and initiates multiple metabolic changes including enhanced insulin sensitivity. However, the function of Myostatin in the heart is barely understood although it is upregulated in the myocardium in several pathological conditions. OBJECTIVE: Here, we aimed to decipher the role of Myostatin and Myostatin-dependent signaling pathways for cardiac function and cardiac metabolism in adult mice. To avoid potential counter-regulatory mechanisms occurring in constitutive and germ-line based Myostatin mutants we generated a mouse model that allows Myostatin inactivation in adult cardiomyocytes. METHODS AND RESULTS: Cardiac MRI revealed that genetic inactivation of Myostatin signaling in the adult murine heart caused cardiac hypertrophy and heart failure partially recapitulating effects of the age-dependent decline of the Myostatin paralogue GDF11. We found that Myostatin represses AMPK activation in the heart via TAK1 thereby preventing a metabolic switch towards glycolysis and glycogen accumulation. Furthermore, Myostatin stimulated expression of Rgs2, a GTPase activating protein that restricts Gaq and Gas signaling and thereby protects against cardiac failure. Inhibition of AMPK in vivo rescued cardiac hypertrophy and prevented enhanced glycolytic flow as well as glycogen accumulation after inactivation of Myostatin in cardiomyocytes. CONCLUSIONS: Our results uncover an important role of Myostatin in the heart for maintaining cardiac energy homeostasis and preventing cardiac hypertrophy.