Role of AMPK in the regulation of protein synthesis and in the development of cardiac hypertrophy

Abstract

The AMP-activated protein kinase (AMPK) is a serine/threonine protein kinase acting as a cellular fuel gauge for the maintenance of energy homeostasis. The contractile activity of the heart being so “energy consuming”, the role of AMPK is central in this organ. It is even more critical under several pathological conditions including myocardial ischemia and cardiac hypertrophy. Among the different cellular processes regulated by AMPK, protein synthesis plays a key role. In this study, we first, evaluated the role of AMPK in the control of the signalling pathways involved in the regulation of protein synthesis, namely eEF2 and p70S6K, under normoxic and ischemic conditions using an AMPKα2 catalytic subunit knockout mouse model. Our results established the critical role of AMPK in the inhibition of the elongation factor eEF2 during ischemia but challenged the usual notion that the ischemia-mediated inhibition of the p70S6K pathway is controlled by AMPK. On the other hand, we showed that the absence of AMPKα2 promoted the stimulation of the p70S6K pathway under normoxic conditions. In the second part of our study, we evaluated the impact of AMPK activation on cardiac hypertrophy in a model of neonatal rat cardiomyocytes treated with the pro-hypertrophic agent phenylephrine. One of the particularities of this study was the use of a specific AMPK activator, the A-769662 compound. We demonstrated that A-769662 prevented the phenylephrine-induced stimulation of protein synthesis and of its regulators eEF2 and p70S6K. Moreover, the phenylephrine-dependent stimulation of two important gene transcription regulation pathways involving the MAP kinase ERK and the transcription factor NFAT was also counteracted by A-769662. Finally, by using a silencing RNA approach, we proved the implication of AMPK in the effect of the A-769662 compound on cardiac hypertrophy. In conclusion, our results provide evidence for the implication of AMPK in the control of various signalling elements involved in the regulation of protein synthesis and gene expression that could play an important role in various cardiac pathologies including myocardial ischemia and hypertrophy. AMPK activation might be a valuable tool for inhibiting or preventing adverse effect of such pathologies.(MED 3) -- UCL, 201