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Cardiac hypertrophy, an adaptive process that responds to increased wall stress, is characterized by the enlargement of cardiomyocytes and structural remodeling. It is stimulated by various growth signals, of which the mTORC1 pathway is a well-recognized source. Here, we show that loss of  Flcn , a novel AMPK–mTOR interacting molecule, causes severe cardiac hypertrophy with deregulated energy homeostasis leading to dilated cardiomyopathy in mice. We found that mTORC1 activity was upregulated in  Flcn -deficient hearts, and that rapamycin treatment significantly reduced heart mass and ameliorated cardiac dysfunction. Phospho-AMP-activated protein kinase (AMPK)-alpha (T172) was reduced in  Flcn -deficient hearts and nonresponsive to various stimulations including metformin and AICAR (5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide). ATP levels were elevated and mitochondrial function was increased in  Flcn -deficient hearts, suggesting that excess energy resulting from up-regulated mitochondrial metabolism under  Flcn  deficiency might attenuate AMPK activation. Expression of Ppargc1a, a central molecule for mitochondrial metabolism, was increased in  Flcn -deficient hearts and indeed, inactivation of  Ppargc1a  in  Flcn -deficient hearts significantly reduced heart mass and prolonged survival.  Ppargc1a  inactivation restored phospho-AMPK-alpha levels and suppressed mTORC1 activity in  Flcn -deficient hearts, suggesting that up-regulated  Ppargc1a  confers increased mitochondrial metabolism and excess energy, leading to inactivation of AMPK and activation of mTORC1. Rapamycin treatment did not affect the heart size of  Flcn/Ppargc1a  doubly inactivated hearts, further supporting the idea that  Ppargc1a  is the critical element leading to deregulation of the AMPK–mTOR-axis and resulting in cardiac hypertrophy under  Flcn  deficiency. These data support an important role for  Flcn  in cardiac homeostasis in the murine model.

Folliculin ( Flcn ) inactivation leads to murine cardiac hypertrophy through mTORC1 deregulation