Spatiotemporal AMPKα2 deletion in mice induces cardiac dysfunction, fibrosis and cardiolipin remodeling associated with mitochondrial dysfunction in males only
| Autor: | Mélanie Gressette, Eric Jacquet, Marta Novotova, Vladimir Veksler, Mathias Mericskay, Kaveen Bedouet, Audrey Solgadi, Ahmed Karoui, Maria-Nieves Sanz, Anne Garnier, Renée Ventura-Clapier, Lucile Grimbert, Catherine Rucker-Martin, Christophe Lemaire, Susana Gomez, Jérôme Piquereau |
|---|---|
| Přispěvatelé: | Signalisation et physiopathologie cardiovasculaire (UMRS1180), Institut National de la Santé et de la Recherche Médicale (INSERM), Hypertension arterielle pulmonaire physiopathologie et innovation thérapeutique, Centre chirurgical Marie Lannelongue-Institut National de la Santé et de la Recherche Médicale (INSERM), Slovak Academy of Sciences (SAS), Institut Paris Saclay d’Innovation Thérapeutique (IPSIT), Université Paris-Sud - Paris 11 (UP11)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie des Substances Naturelles (ICSN), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), JACQUET, ERIC, Metabolic therapy of heart failure: which place for a cocktail of B vitamins? - - HF-MetaB2019 - ANR-19-ECVD-0007 - ERA-CVD - VALID, Centre Chirurgical Marie Lannelongue (CCML)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), This study was supported by the Slovak Research and Development Agency grant (M.N., APVV-15-0302), and by the Slovak Scientific Grant Agency (M.N., VEGA 2/0091/19). R.V.-C is emeritus scientist at CNRS., ANR-19-ECVD-0007,HF-MetaB,Metabolic therapy of heart failure: which place for a cocktail of B vitamins?(2019) |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
Cardiac function curve medicine.medical_specialty Heart Diseases Cardiac fibrosis Cardiolipins Physiology [SDV]Life Sciences [q-bio] 030204 cardiovascular system & hematology Gender Studies Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Endocrinology AMP-activated protein kinase Fibrosis Internal medicine medicine Cardiolipin Animals QP1-981 Protein kinase A 030304 developmental biology Mice Knockout 0303 health sciences biology business.industry Research AMPK Heart Energy metabolism medicine.disease Mitochondria [SDV] Life Sciences [q-bio] chemistry Heart failure biology.protein cardiovascular system Medicine Female business |
| Zdroj: | Biology of Sex Differences, Vol 12, Iss 1, Pp 1-24 (2021) Biology of Sex Differences Biology of Sex Differences, BioMed Central, 2021, 12 (1), ⟨10.1186/s13293-021-00394-z⟩ Biology of Sex Differences, 2021, 12 (1), ⟨10.1186/s13293-021-00394-z⟩ |
| ISSN: | 2042-6410 |
| DOI: | 10.1186/s13293-021-00394-z⟩ |
| Popis: | 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. Highlights AMPK is a metabolic sensor of cellular energy which regulates energy homeostasis.We generated a cardiac-specific inducible deletion of Ampkα2 and demonstrated that this deletion induces mild cardiac dysfunction in male only.Cardiac dysfunction observed in males was associated with cardiac fibrosis and cardiac cardiolipin remodeling that are not seen in females.Although no significant cardiac function alteration was noticed in ovariectomized female Ampkα2ciKO mice, these latter exhibited cardiac fibrosis and mild cardiolipins remodeling.Our results show a higher dependence on AMPK signaling fibrosis and cardiolipin biosynthesis/maturation in males, either due to the absence of female hormones protection or/and to the action of male hormones. This may contribute to the known difference in cardiovascular risk and outcome between sexes. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|