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Dilated cardiomyopathy impairs mitochondrial biogenesis and promotes inflammation in an age- and sex-dependent manner.

ABSTRACT: Dilated cardiomyopathy (DCM) belongs to the myocardial diseases associated with a severe impairment of cardiac function, but the question of how sex and age affect this pathology has not been fully explored. Impaired energy homeostasis, mitochondrial dysfunction, and systemic inflammation are well-described phenomena associated with aging. In this study, we investigated if DCM affects these phenomena in a sex- and age-related manner. We analyzed the expression of mitochondrial and antioxidant proteins and the inflammatory state in DCM heart tissue from younger and older women and men. A significant downregulation of Sirt1 expression was detected in older DCM patients. Sex-related differences were observed in the phosphorylation of AMPK that only appeared in older males with DCM, possibly due to an alternative Sirt1 regulation mechanism. Furthermore, reduced expression of several mitochondrial proteins (TOM40, TIM23, Sirt3, and SOD2) and genes (cox1, nd4) was only detected in old DCM patients, suggesting that age has a greater effect than DCM on these alterations. Finally, an increased expression of inflammatory markers in older, failing hearts, with a stronger pro-inflammatory response in men, was observed. Together, these findings indicate that age- and sex-related increased inflammation and disturbance of mitochondrial homeostasis occurs in male individuals with DCM.

SUBMITTER: Barcena ML

PROVIDER: S-EPMC7762497 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Dilated cardiomyopathy impairs mitochondrial biogenesis and promotes inflammation in an age- and sex-dependent manner.

Barcena Maria Luisa ML Pozdniakova Sofya S Haritonow Natalie N Breiter Pavelas P Kühl Anja A AA Milting Hendrik H Baczko Istvan I Ladilov Yury Y Regitz-Zagrosek Vera V

Aging 20201202 23

Dilated cardiomyopathy (DCM) belongs to the myocardial diseases associated with a severe impairment of cardiac function, but the question of how sex and age affect this pathology has not been fully explored. Impaired energy homeostasis, mitochondrial dysfunction, and systemic inflammation are well-described phenomena associated with aging. In this study, we investigated if DCM affects these phenomena in a sex- and age-related manner. We analyzed the expression of mitochondrial and antioxidant pr ...[more]

PMID: 33303703

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Project description:RationaleThe E2F pathway plays a critical role in cardiac growth and development, yet its role in cardiac metabolism remains to be defined. Metabolic changes play important roles in human heart failure and studies imply the ketogenic enzyme ?-hydroxybutyrate dehydrogenase I (BDH1) is a potential biomarker.ObjectiveTo define the role of the E2F pathway in cardiac metabolism and dilated cardiomyopathy (DCM) with a focus on BDH1.Methods and resultsWe previously developed transgenic (Tg) mice expressing the transcriptional repressor, E2F6, to interfere with the E2F/Rb pathway in post-natal myocardium. These Tg mice present with an E2F6 dose dependent DCM and deregulated connexin-43 (CX-43) levels in myocardium. Using the Seahorse platform, a 22% decrease in glycolysis was noted in neonatal cardiomyocytes isolated from E2F6-Tg hearts. This was associated with a 39% reduction in the glucose transporter GLUT4 and 50% less activation of the regulator of glucose metabolism AKT2. The specific reduction of cyclin B1 (70%) in Tg myocardium implicates its importance in supporting glycolysis in the postnatal heart. No changes in cyclin D expression (known to regulate mitochondrial activity) were noted and lipid metabolism remained unchanged in neonatal cardiomyocytes from Tg hearts. However, E2F6 induced a 40-fold increase of the Bdh1 transcript and 890% increase in its protein levels in hearts from Tg pups implying a potential impact on ketolysis. By contrast, BDH1 expression is not activated until adulthood in normal myocardium. Neonatal cardiomyocytes from Wt hearts incubated with the ketone ?-hydroxybutyrate (?-OHB) showed a 100% increase in CX-43 protein levels, implying a role for ketone signaling in gap junction biology. Neonatal cardiomyocyte cultures from Tg hearts exhibited enhanced levels of BDH1 and CX-43 and were not responsive to ?-OHB.ConclusionsThe data reveal a novel role for the E2F pathway in regulating glycolysis in the developing myocardium through a mechanism involving cyclin B1. We reveal BDH1 expression as an early biomarker of heart failure and its potential impact, through ketone signaling, on CX-43 levels in E2F6-induced DCM.

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Dilated cardiomyopathy impairs mitochondrial biogenesis and promotes inflammation in an age- and sex-dependent manner.

Publications

Dilated cardiomyopathy impairs mitochondrial biogenesis and promotes inflammation in an age- and sex-dependent manner.

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