Spatiotemporal AMPK\u03b12 deletion in mice induces cardiac dysfunction, fibrosis and cardiolipin remodeling associated with mitochondrial dysfunction in males only

Lucile Grimbert,Vladimir Veksler,Jérôme Piquereau,Kaveen Bedouet,Mathias Mericskay,Audrey Solgadi,Susana Gomez,Ahmed Karoui,Anne Garnier,Marta Novotova,Christophe Lemaire,Catherine Rucker-Martin,Renée Ventura-Clapier,Eric Jacquet,Mélanie Gressette,Maria-Nieves Sanz

doi:10.1186/s13293-021-00394-z

Abstract

BackgroundThe 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.MethodsTo 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.ResultsCardio-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.ConclusionOur 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

The AMP-activated protein kinase (AMPK) is a ubiquitous serine/threonine kinase which acts as a cellular “fuel gauge” regulating energy homeostasis [1]
The remnant 70% phospho-AMPK signal comes most probably mostly from phosphorylated AMPKα1. Even though this set of data could suggest a decrease in AMPK activity, phosphorylation of acetyl-CoA carboxylase (ACC), a target of AMPKα1/ AMPKα2, was not significantly different between all groups while the total amount of ACC was unchanged in Ampkα2ciKO mice (Fig. 1B)
None of the deleterious effects on cardiac function observed in males were due to a potential toxicity of Cre recombinase since our team already demonstrated that the tamoxifen conditions used for inducing gene deletion do not impact cardiac function in αMHC-MerCreMer mice [37]

Summary

Introduction

The AMP-activated protein kinase (AMPK) is a ubiquitous serine/threonine kinase which acts as a cellular “fuel gauge” regulating energy homeostasis [1]. This kinase is composed of a catalytic subunit (α) and two regulatory subunits (β and γ), each including several isoforms exhibiting differential tissue expression. 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 AMPKKO in peripheral organs. 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

Methods

Results

Conclusion