Spatiotemporal AMPKα2 deletion in mice induces cardiac dysfunction, fibrosis and cardiolipin remodeling associated with mitochondrial dysfunction in males only.

Autor: Grimbert L; Faculté de Pharmacie, UMR-S1180, INSERM, Université Paris-Saclay, 5 rue J-B Clément, 92296, Châtenay-Malabry, France., Sanz MN; Faculté de Pharmacie, UMR-S1180, INSERM, Université Paris-Saclay, 5 rue J-B Clément, 92296, Châtenay-Malabry, France., Gressette M; Faculté de Pharmacie, UMR-S1180, INSERM, Université Paris-Saclay, 5 rue J-B Clément, 92296, Châtenay-Malabry, France., Rucker-Martin C; Université Paris-Saclay, Inserm, Hypertension Artérielle Pulmonaire: Physiopathologie et Innovation Thérapeutique, 92350, Le Plessis Robinson, France., Novotova M; Department of Cellular Cardiology, Institute of Experimental Endocrinology, Biomedical Research Center, University Science Park for Biomedicine, Slovak Academy of Sciences, Bratislava, Slovakia., Solgadi A; Service d'Analyse des Médicaments et Métabolites, Université Paris-Saclay, Inserm, CNRS, Institut Paris Saclay d'Innovation Thérapeutique, 92296, Châtenay-Malabry, France., Karoui A; Faculté de Pharmacie, UMR-S1180, INSERM, Université Paris-Saclay, 5 rue J-B Clément, 92296, Châtenay-Malabry, France., Gomez S; Faculté de Pharmacie, UMR-S1180, INSERM, Université Paris-Saclay, 5 rue J-B Clément, 92296, Châtenay-Malabry, France., Bedouet K; Faculté de Pharmacie, UMR-S1180, INSERM, Université Paris-Saclay, 5 rue J-B Clément, 92296, Châtenay-Malabry, France., Jacquet E; Université Paris-Saclay, CNRS, Institut de Chimie Des Substances Naturelles, UPR 2301, 91198, Gif-sur-Yvette, France., Lemaire C; Faculté de Pharmacie, UMR-S1180, INSERM, Université Paris-Saclay, 5 rue J-B Clément, 92296, Châtenay-Malabry, France.; Université Versailles St-Quentin, Université Paris-Saclay, Inserm, UMR-S 1180, 92296, Châtenay-Malabry, France., Veksler V; Faculté de Pharmacie, UMR-S1180, INSERM, Université Paris-Saclay, 5 rue J-B Clément, 92296, Châtenay-Malabry, France., Mericskay M; Faculté de Pharmacie, UMR-S1180, INSERM, Université Paris-Saclay, 5 rue J-B Clément, 92296, Châtenay-Malabry, France., Ventura-Clapier R; Faculté de Pharmacie, UMR-S1180, INSERM, Université Paris-Saclay, 5 rue J-B Clément, 92296, Châtenay-Malabry, France., Piquereau J; Faculté de Pharmacie, UMR-S1180, INSERM, Université Paris-Saclay, 5 rue J-B Clément, 92296, Châtenay-Malabry, France. jerome.piquereau@universite-paris-saclay.fr., Garnier A; Faculté de Pharmacie, UMR-S1180, INSERM, Université Paris-Saclay, 5 rue J-B Clément, 92296, Châtenay-Malabry, France.
Jazyk: angličtina
Zdroj: Biology of sex differences [Biol Sex Differ] 2021 Sep 17; Vol. 12 (1), pp. 52. Date of Electronic Publication: 2021 Sep 17.
DOI: 10.1186/s13293-021-00394-z
Abstrakt: Background: The AMP-activated protein kinase (AMPK) is a major regulator of cellular energetics which plays key role in acute metabolic response and in long-term adaptation to stress. Recent works have also suggested non-metabolic effects.
Methods: To decipher AMPK roles in the heart, we generated a cardio-specific inducible model of gene deletion of the main cardiac catalytic subunit of AMPK (Ampkα2) in mice. This allowed us to avoid the eventual impact of AMPK-KO in peripheral organs.
Results: Cardio-specific Ampkα2 deficiency led to a progressive left ventricular systolic dysfunction and the development of cardiac fibrosis in males. We observed a reduction in complex I-driven respiration without change in mitochondrial mass or in vitro complex I activity, associated with a rearrangement of the cardiolipins and reduced integration of complex I into the electron transport chain supercomplexes. Strikingly, none of these defects were present in females. Interestingly, suppression of estradiol signaling by ovariectomy partially mimicked the male sensitivity to AMPK loss, notably the cardiac fibrosis and the rearrangement of cardiolipins, but not the cardiac function that remained protected.
Conclusion: Our results confirm the close link between AMPK and cardiac mitochondrial function, but also highlight links with cardiac fibrosis. Importantly, we show that AMPK is differently involved in these processes in males and females, which may have clinical implications for the use of AMPK activators in the treatment of heart failure.
(© 2021. The Author(s).)
Databáze: MEDLINE
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