Calorie restriction anti-hypertrophic effects are associated with improved mitochondrial content, blockage of Ca²⁺-induced mitochondrial damage, and lower reverse electron transport-mediated oxidative stress

Abstract

Calorie restriction is a nutritional intervention that reproducibly protects against the maladaptive consequences of cardiovascular diseases. Pathological cardiac hypertrophy leads to cellular growth, dysfunction (with mitochondrial dysregulation), and oxidative stress. The mechanisms behind the cardiovascular protective effects of calorie restriction are still under investigation. In this study, we show that this dietetic intervention prevents cardiac protein elevation, avoids fetal gene reprogramming (atrial natriuretic peptide), and blocks the increase in heart weight per tibia length index (HW/TL) seen in isoproterenol-induced cardiac hypertrophy. Our findings suggest that calorie restriction inhibits cardiac pathological growth while also lowering mitochondrial reverse electron transport-induced hydrogen peroxide formation and improving mitochondrial content. Calorie restriction also attenuated the opening of the Ca²⁺-induced mitochondrial permeability transition pore. We also found that calorie restriction blocked the negative correlation of antioxidant enzymes (superoxide dimutase and glutatione peroxidase activity) and HW/TL, leading to the maintenance of protein sulphydryls and glutathione levels. Given the nature of isoproterenol-induced cardiac hypertrophy, we investigated whether calorie restriction could alter cardiac beta-adrenergic sensitivity. Using isolated rat hearts in a Langendorff system, we found that calorie restricted hearts have preserved beta-adrenergic signaling. In contrast, hypertrophic hearts (treated for seven days with isoproterenol) were insensitive to beta-adrenergic activation using isoproterenol (50 nM). Despite protecting against cardiac hypertrophy, calorie restriction did not alter the lack of responsiveness to isoproterenol in isolated hearts harvested from isoproterenol-treated rats. These results suggest (through a series of mitochondrial, oxidative stress, and cardiac hemodynamic studies) that calorie restriction possesses beneficial effects against hypertrophic cardiomyopathy.

Keywords:

• Mitochondria
• calorie restriction
• cardiac hypertrophy
• oxidative stress
• adrenergic signaling

Acknowledgements

The authors acknowledge the technical assistance of Anna Lidia Nunes Varela, Iuliana Marjory Martins Ribeiro, and Antônio F. R. Santos. The authors would like to thank Dr. Marcus Oliveira for his helpful discussions and critical evaluation of the manuscript.

Authors’ contributions

Study concept and design: Heberty T Facundo; Aline Maria Brito Lucas; Data acquisition: Plinio Bezerra Palacio, Pedro Lourenzo Oliveira Cunha, Aline Maria Brito Lucas; Data analysis: Aline Maria Brito Lucas and Heberty T Facundo. Heberty T Facundo wrote the paper, which was critically reviewed by all authors. All authors read and approved the final manuscript.

Disclosure statement

The authors declare no competing financial interests or personal relationships that could influence the work reported in this paper.

Ethical approval

All procedures were approved by the Institutional Animal Experimentation Ethics Committee of the Universidade Federal do Cariri under protocol number (001/2017).

Data availability statement

Data will be made available on reasonable request.

Additional information

Funding

Pedro Lourenzo Oliveira Cunha is a recipient of research scholarships from UFCA. Plinio Bezerra Palacio is a scholarship holder from Fundação Cearense de Apoio ao Desenvolvimento Científico e Tecnológico (FUNCAP). This research was supported by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES/Brasil code 001) and Fundação Cearense de Apoio ao Desenvolvimento Científico e Tecnológico (FUNCAP) and CAPES (grant number 88887.166577/2018-00, finance code: 001), by the Conselho Nacional de Desenvolvimento Científico e Tecnológico – CNPq to Heberty Tarso Facundo (Grant number 409489/2018-2) and by UFCA (Edital ConsolidaPG).