Clin Res Cardiol (2022). https://doi.org/10.1007/s00392-022-02087-y

Disturbance of the cardiac mitochondrial biogenesis, autophagy and pro-inflammatory shift in old women with myocarditis-related cardiomyopathy

G. Tonini1, M. L. Barcena2, P. Breiter2, N. Haritonow2, M. O. Estepa Martinez3, H. Milting4, I. Baczko2, U. Müller-Werdan5, Y. Ladilov2, V. Regitz-Zagrosek6

1CC 11: Med. Klinik für Kardiologie, Charité - Universitätsmedizin Berlin, Berlin; 2Medizinische Klinik für Geriatrie und Altersmedizin, Charité - Universitätsmedizin Berlin, Berlin; 3Klinik für Innere Medizin - Kardiologie, Deutsches Herzzentrum Berlin, Berlin; 4E.& H. Klessmann-Institut f. kardiovask. Forschung, Herz- und Diabeteszentrum NRW, Bad Oeynhausen; 5Klinik für Geriatrie und Altersmedizin, Charité - Universitätsmedizin Berlin, Berlin; 6Institut für Geschlechterforschung in der Medizin (GiM), Charité - Universitätsmedizin Berlin, Berlin;

Introduction: Myocarditis is a cardiovascular disease, which is accompanied by inflammation, mitochondrial dysfunction, autophagy impairment and in the late stage by the development of heart failure. Age and sex differences in heart failure development have been postulated. However, the underlying molecular mechanisms of these differences are still poorly understood. In the current study, we aimed to investigate, whether sex and age are involved in mitochondrial biogenesis and the inflammatory state in myocarditis-related cardiomyopathy. We propose age-dependent sex differences in the AMPK activation, expression of mitochondrial proteins and autophagy markers in hearts of patients with end-stage myocarditis that may promote chronic cardiac inflammation in myocarditis. Methods: Human lateral left ventricular wall tissue from young and old patients with myocarditis-related cardiomyopathy (men= 20 and women= 15) and from healthy individuals (men= 16 and women= 15) were used for qRT-PCR and western blot analysis. Expression of Sirt1, phosphorylated AMPK, PGC-1α, Sirt3, acetylated SOD, catalase and several mitochondrial genes were analyzed. NFkB and IL-18 were used to examine the inflammatory state in the heart. Moreover, the autophagy marker, ATG5, LC3I, LC3II and p62 were analyzed using western blot analysis. Results: AMPK and Sirt1, are two key cellular energy sensors and regulators of mitochondrial homeostasis. Myocardial AMPK expression and activity were significantly elevated in male myocarditis patients, whereas Sirt1 remained unchanged in all groups investigated. The elevated AMPK expression and activity preserved expression of all mitochondrial proteins/genes investigated in old male myocarditis patients, whereas it was significantly reduced in old female patients, e.g., mitochondrial import proteins TOM40 and TIM23 and mitochondrial oxidative phosphorylation genes cox1 nd4 and ndusf1. Noteworthy, mitochondrial acetylation state (indicated by acetylated SOD2) was significantly reduced in old male, but not in old female myocarditis patients. This argues for a better function of mitochondrial enzymes, in particular anti-oxidative enzyme SOD2, in male hearts. In addition, ATG-5 is significantly increased in old myocarditis hearts at RNA and protein levels. P62 is also increased in myocardial tissue in old myocarditis men. LC3I and LC3II were increased in old myocarditis men when compared to young myocarditis male. Analysis of inflammation markers revealed downregulation of NFkB (a key pro-inflammatory transcription factor) in old male myocarditis patients, whereas expression of the pro-inflammatory IL-18 was increased in old female patients. Conclusion: Elderly female patients suffer from decreased expression of mitochondrial biogenesis, i.e., decreased expression of mitochondrial proteins. In contrast, mitochondrial biogenesis is preserved in the hearts of old male patients, probably because of increased AMPK expression and activity. Of note, mitochondrial homeostasis in this patient group is supported by reduced mitochondrial acetylation status and enhanced mitochondrial antioxidant defense (SOD2). Impaired mitochondrial homeostasis in aged women's hearts with myocarditis is accompanied by a pro-inflammatory shift. The data suggest a strategy to ameliorate the dysregulation of mitochondrial biogenesis and the proinflammatory shift in aged female myocarditis patients by treatment with AMPK activators.

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