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

Abstract

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.

ALCAT1-mediated abnormal cardiolipin remodelling promotes mitochondrial injury in podocytes in diabetic kidney disease

“…Therefore, our findings suggested that ALCAT1 induced podocyte mitochondrial malfunction through the AMPK pathway. Some studies have reported that the knockout of AMPK may affect the expression of cardiolipin-related synthetic enzymes by possibly influencing the PGC-1α/ERRα axis, and this may be related to the role of AMPK in basal conditions [ 58 ]. In our research, the intervention with ALCAT1 did not affect the overall expression of AMPK but did impact the phosphorylated expression of AMPK.…”

Modulation of cardiac cAMP signaling by AMPK and its adjustments in pressure overload-induced myocardial dysfunction in rat and mouse

“…Global and constitutive deletion of the α2 subunit of AMPK does not induce overt cardiac defects in mice until the age of 17 weeks. Our mice thus display a milder cardiac phenotype than inducible cardiac-specific AMPKα2 knockout mice, which show impairment of cardiac contractile function and cardiac fibrosis two months after AMPKα2 deletion in the adulthood [ 8 ]. Our results are in accordance with previous studies showing that global and constitutive AMPKα2-/- mice do not exhibit anatomical or hemodynamic alteration nor decreased oxygen consumption or contractile dysfunction in isolated perfused hearts [ 16 , 32 ].…”

“…Newly revealed roles for AMPK further established its place at the heart of energy metabolism [ 6 ]. It is now also recognised that AMPK activity is critical for the cardiolipin composition of mitochondrial membranes, which affects the function of the mitochondrial respiratory chain [ 7 , 8 ]. AMPK is mainly present in the cytoplasm but complexes containing the α2 subunit are also present in the nucleus, where they modulate gene expression [ 9 ].…”