Substrate metabolism regulated by Sestrin2–mTORC1 alleviates pressure overload-induced cardiac hypertrophy in aged heart

Sestrin2 (Sesn2) is a stress sensor for the mammalian target of rapamycin complex 1 (mTORC1) pathway. Aging impairs cardiac mTORC1 activation, thereby sensitizing the heart to hypertrophy. C57BL/6 J young wild-type (young WT; 4–6 months), aged WT (24–26 months), and young Sestrin2 knockout mice (Y-Sesn2 KO; 4–6 months) underwent transverse aortic constriction (TAC) for pressure overload. Cardiac expression of Sesn2 decreased with age. At 4 weeks after TAC, aged WT and Y-Sesn2 KO exhibited larger hearts and impaired cardiac function, compared with young WT mice. Augmented phosphorylation of mTOR and downstream effectors; damaged mitochondria and elevated redox markers, as well as and impaired glucose and fatty acid oxidation were observed in aged WT and Y-Sesn2 KO hearts. A pressure overload-induced interaction between Sesn2 and GTPase-activating protein activity toward Rags 2 (GATOR2), which positively regulates mTORC1, was impaired in aged WT hearts. Adeno-associated virus 9–Sesn2 treatment rescued Sesn2 expression, attenuated mTORC1 activation, and increased pressure overload tolerance in aged WT and Y-Sesn2 KO hearts. These results indicated that cardiac Sesn2 acts as a pressure overload sensor for mTORC1. Furthermore, Sesn2 deficiency may cause increased sensitivity to hypertrophy in elderly individuals.