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Activation or inactivation of cardiac Akt/mTOR signaling diverges physiological from pathological hypertrophy
Author(s) -
Kemi Ole Johan,
Ceci Marcello,
Wisloff Ulrik,
Grimaldi Serena,
Gallo Paolo,
Smith Godfrey L,
Condorelli Gianluigi,
Ellingsen Oyvind
Publication year - 2008
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.21197
Subject(s) - pressure overload , protein kinase b , muscle hypertrophy , pi3k/akt/mtor pathway , medicine , endocrinology , p70 s6 kinase 1 , phosphorylation , biology , chemistry , signal transduction , microbiology and biotechnology , cardiac hypertrophy
Abstract Cardiomyocyte hypertrophy differs according to the stress exerted on the myocardium. While pressure overload‐induced cardiomyocyte hypertrophy is associated with depressed contractile function, physiological hypertrophy after exercise training associates with preserved or increased inotropy. We determined the activation state of myocardial Akt signaling with downstream substrates and fetal gene reactivation in exercise‐induced physiological and pressure overload‐induced pathological hypertrophies. C57BL/6J mice were either treadmill trained for 6 weeks, 5 days/week, at 85–90% of maximal oxygen uptake (VO 2max ), or underwent transverse aortic constriction (TAC) for 1 or 8 weeks. Total and phosphorylated protein levels were determined with SDS‐PAGE, and fetal genes by real‐time RT‐PCR. In the physiologically hypertrophied heart after exercise training, total Akt protein level was unchanged, but Akt was chronically hyperphosphorylated at serine 473. This was accompanied by activation of the mammalian target of rapamycin (mTOR), measured as phosphorylation of its two substrates: the ribosomal protein S6 kinase‐1 (S6K1) and the eukaryotic translation initiation factor‐4E binding protein‐1 (4E‐BP1). Exercise training did not reactivate the fetal gene program (β‐myosin heavy chain, atrial natriuretic factor, skeletal muscle actin). In contrast, pressure overload after TAC reactivated fetal genes already after 1 week, and partially inactivated the Akt/mTOR pathway and downstream substrates after 8 weeks. In conclusion, changes in opposite directions of the myocardial Akt/mTOR signal pathway appears to distinguish between physiological and pathological hypertrophies; exercise training associating with activation and pressure overload associating with inactivation of the Akt/mTOR pathway. J. Cell. Physiol. 214: 316–321, 2008. © 2007 Wiley‐Liss, Inc.