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Dual cardiac contractile effects of the ₂-AMPK deletion in low-flow ischemia and reperfusion

¹INSERM U769, Faculté de Pharmacie, Université Paris-Sud, Châtenay-Malabry, France; ²Division of Cardiology, School of Medecine, Université Catholique de Louvain, Brussels, Belgium; ³RMN Biologique, Institut de Chimie des Substances Naturelles, Centre National de la Recherche Scientifique, Gif sur Yvette, France; and ⁴Institut Cochin, INSERM U567, Centre National de la Recherche Scientifique UMR-8104, Université Paris 5, Paris, France; and ⁵Département des Facteurs Humains, Centre Recherche Service Santé Armée, La Tronche, France

Submitted 28 June 2006 ; accepted in final form 8 February 2007

Because the question "is AMP-activated protein kinase (AMPK) ₂-isoform a friend or a foe in the protection of the myocardium against ischemia-reperfusion injury?" is still in debate, we studied the functional consequence of its deletion on the contractility, the energetics, and the respiration of the isolated perfused heart and characterized the response to low-flow ischemia and reperfusion with glucose and pyruvate as substrates. ₂-AMPK deletion did not affect basal contractility, respiration, and high-energy phosphate contents but induced a twofold reduction in glycogen content and a threefold reduction in glucose uptake. Low-flow ischemia increased AMPK phosphorylation and stimulated glucose uptake and phosphorylation in both ₂-knockout (₂-KO) and wild-type (WT) groups. The high sensitivity of ₂-KO to the development of ischemic contracture was attributed to the constitutive impairment in glucose transport and glycogen content and not to a perturbation of the energy transfer by creatine kinase (CK). The functional coupling of MM-CK to myofibrillar ATPase and the CK fluxes were indeed similar in ₂-KO and WT. Low-flow ischemia impaired CK flux by 50% in both strains, showing that ₂-AMPK does not control CK activity. Despite the higher sensitivity to contracture, the postischemic contractility recovered to similar levels in both ₂-KO and WT in the absence of fatty acids. In their presence, ₂-AMPK deletion also accelerated the contracture but delayed postischemic contractile recovery. In conclusion, ₂-AMPK is required for a normal glucose uptake and glycogen content, which protects the heart from the development of the ischemic contracture, but not for contractile recovery in the absence of fatty acids.

glucose uptake; pyruvate; fatty acids; energetics; rigor; creatine kinase; ³¹P-NMR spectroscopy; energetic cost of contractility

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