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Mitochondrial adaptations in liver and skeletal muscle to pro-longevity nutritional and genetic interventions: the crosstalk between calorie restriction and CYB5R3 overexpression in transgenic mice

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Abstract

Calorie restriction without malnutrition (CR) is considered as the most effective nongenetic nor pharmacological intervention that promotes healthy aging phenotypes and can extend lifespan in most model organisms. Lifelong CR leads to an increase of cytochrome b5 reductase-3 (CYB5R3) expression and activity. Overexpression of CYB5R3 confers some of the salutary effects of CR, although the mechanisms involved might be independent because key aspects of energy metabolism and lipid profiles of tissues go in opposite ways. It is thus important to study if some of the metabolic adaptations induced by CR are affected by CYB5R3 overexpression. CYB5R3 overexpression greatly preserved body and liver weight in mice under CR conditions. In liver, CR did not modify mitochondrial abundance, but lead to increased expression of mitofusin Mfn2 and TFAM, a transcription factor involved in mitochondrial biogenesis. These changes were prevented by CYB5R3 overexpression but resulted in a decreased expression of a different mitochondrial biogenesis-related transcription factor, Nrf1. In skeletal muscle, CR strongly increased mitochondrial mass, mitofusin Mfn1, and Nrf1. However, CYB5R3 mice on CR did not show increase in muscle mitochondrial mass, regardless of a clear increase in expression of TFAM and mitochondrial complexes in this tissue. Our results support that CYB5R3 overexpression significantly modifies the metabolic adaptations of mice to CR.

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Funding

This study was supported by Spanish Ministerio de Economía y Competitividad (MINECO) grant BFU2015-64630-R, cofinanced with EU FEDER funds, and Ministerio de Ciencia, Innovación y Universidades (MICIU) grant RTI2018-100695-B-I00, Spanish Junta de Andalucía (BIO-276) and Universidad de Córdoba (to JMVM). SRL held a FPI predoctoral contract funded by MINECO. SLB held a FPU predoctoral contract awarded by the Spanish Ministerio de Educación, Cultura y Deporte (MECD). RdC is supported by the Intramural Research Program of the National Institute on Aging.

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Contributions

JMVM and RdC conceived and designed the project; SRL was responsible of raising and maintaining the colony of mice; SRL and SLB performed the experimental determinations and conducted the data analysis; JAGR and MIB provided valuable advice; SRL, SLB and JMVM wrote the manuscript with approval from all authors.

Corresponding author

Correspondence to José M. Villalba.

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All animals were cared for in accordance with the University of Córdoba policy for animal welfare, which complies current European, Spanish and Andalusian regulations and is in accordance with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health. This study was approved by the bioethics committee of the University of Córdoba and authorized by the Consejería de Agricultura, Pesca y Desarrollo Rural, Junta de Andalucía (authorization code: 20/04/2016/053).

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The authors declare that they have no conflicts of interest.

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Rodríguez-López, S., López-Bellón, S., González-Reyes, J.A. et al. Mitochondrial adaptations in liver and skeletal muscle to pro-longevity nutritional and genetic interventions: the crosstalk between calorie restriction and CYB5R3 overexpression in transgenic mice. GeroScience 42, 977–994 (2020). https://doi.org/10.1007/s11357-020-00187-z

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  • DOI: https://doi.org/10.1007/s11357-020-00187-z

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