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

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 themTORC1 pathway is awell-recognized source.Here,weshowthat loss of Flcn, a novelAMPK-mTORinteractingmolecule, 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 reducedheartmass andamelioratedcardiacdysfunction.Phospho-AMP-activatedprotein kinase (AMPK)-alpha (T172) was reduced in Flcn-deficient hearts and nonresponsive to various stimulations including metformin and AICAR (5-amino-1-b-D-ribofuranosyl-imidazole-4-carboxamide). ATP levels were elevated andmitochondrial functionwas increased in Flcn-deficient hearts, suggesting that excess energy resulting fromup-regulatedmitochondrialmetabolismunder Flcn deficiencymight attenuateAMPKactivation.Expression of Ppargc1a, a centralmolecule formitochondrialmetabolism, 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 heartsizeof Flcn/Ppargc1adoubly inactivatedhearts, furthersupportingtheideathatPpargc1ais thecriticalelement 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 themurinemodel.