Carbon Monoxide Improves Cardiac Function and Mitochondrial Population Quality in a Mouse Model of Metabolic Syndrome

Steve Lancel,Camille Marciniak,Brigitte Decoster,Delphine Corseaux,Sidi Mohamed Hassoun,Xavier Marechal,Roberto Motterlini,David Montaigne,Remi Neviere,Caroline Blazejewski,Bernadette Lescure,Caroline Ballot,Krisztian Stadler

doi:10.1371/journal.pone.0041836

Steve Lancel, Camille Marciniak + Show 11 more

Open Access

https://doi.org/10.1371/journal.pone.0041836

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Abstract

AimsMetabolic syndrome induces cardiac dysfunction associated with mitochondria abnormalities. As low levels of carbon monoxide (CO) may improve myocardial and mitochondrial activities, we tested whether a CO-releasing molecule (CORM-3) reverses metabolic syndrome-induced cardiac alteration through changes in mitochondrial biogenesis, dynamics and autophagy.Methods and ResultsMice were fed with normal diet (ND) or high-fat diet (HFD) for twelve weeks. Then, mice received two intraperitoneal injections of CORM-3 (10 mg.kg−1), with the second one given 16 hours after the first. Contractile function in isolated hearts and mitochondrial parameters were evaluated 24 hours after the last injection. Mitochondrial population was explored by electron microscopy. Changes in mitochondrial dynamics, biogenesis and autophagy were assessed by western-blot and RT-qPCR. Left ventricular developed pressure was reduced in HFD hearts. Mitochondria from HFD hearts presented reduced membrane potential and diminished ADP-coupled respiration. CORM-3 restored both cardiac and mitochondrial functions. Size and number of mitochondria increased in the HFD hearts but not in the CORM-3–treated HFD group. CORM-3 modulated HFD-activated mitochondrial fusion and biogenesis signalling. While autophagy was not activated in the HFD group, CORM-3 increased the autophagy marker LC3-II. Finally, ex vivo experiments demonstrated that autophagy inhibition by 3-methyladenine abolished the cardioprotective effects of CORM-3.ConclusionCORM-3 may modulate pathways controlling mitochondrial quality, thus leading to improvements of mitochondrial efficiency and HFD-induced cardiac dysfunction.

Highlights

Cardiac mitochondria biogenesis is stimulated in the context of diabetes and appears to be maladaptive as cardiac energy production remains insufficient [5], these three signalling pathways regulating mitochondria quality are not well characterized in cardiac dysfunction that occurs during metabolic syndrome
We previously demonstrated that CORM-3 exerts cardioprotective effects by increasing mitochondrial function and biogenesis during experimental sepsis [12]
The body weight increased in both groups but after 2 months of feeding, the gain of weight was about 53% in the high-fat diet (HFD) compared to 15% in the normal diet (ND) mice (Table S2)

Summary

Introduction

I.e. reduced glucose utilization and enhanced fatty acid metabolism, and functional and structural alterations of the mitochondrial population are among the important mechanisms involved in this form of myocardial dysfunction [1]. Mitochondrial network dynamics as well as a balance between biogenesis of new mitochondria and autophagy of damaged organelles control quality of the mitochondrial population. Dysregulations of these three pathways may have direct consequences on cardiac function. Regarding the autophagy process, cardiac specific Atg5-deficient mice display disorganized sarcomeres and mitochondrial accumulation along with myocardial dysfunction [4]. Cardiac mitochondria biogenesis is stimulated in the context of diabetes and appears to be maladaptive as cardiac energy production remains insufficient [5], these three signalling pathways regulating mitochondria quality are not well characterized in cardiac dysfunction that occurs during metabolic syndrome

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