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miR-146a-5p modulates cellular senescence and apoptosis in visceral adipose tissue of long-lived Ames dwarf mice and in cultured pre-adipocytes

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Abstract

MicroRNAs (miRNAs) are potent regulators of multiple biological processes. Previous studies have demonstrated that miR-146a-5p increases in normal mice during aging, while long-living Ames dwarf (df/df) mice maintain youthful levels of this miRNA. The aim of this study was to elucidate the involvement of miR-146a-5p in modulating cellular senescence and apoptosis in visceral adipose tissue of df/df mice and cultured pre-adipocytes. To test the effects of miR-146a-5p overexpression on visceral adipose tissue, wild-type, and df/df mice, were treated with miRNA-negative control-base and df/df were transfected with 4 or 8 µg/g of a miR-146a-5p mimetic, respectively. Effects of miR-146a-5p overexpression were also evaluated in 3T3-L1 cells cultured under high and normal glucose conditions. Treatment with miR-146a-5p mimetic increased cellular senescence and inflammation and decreased pro-apoptotic factors in visceral adipose tissue of df/df mice. The miR-146a-5p mimetic induced similar effects in 3T3-L1 cells cultivated at normal but not high glucose levels. Importantly, 3T3-L1 HG cells in high glucose conditions showed significantly higher expression of miR-146a-5p than 3T3-L1 grown in normal glucose conditions. These results indicate that miR-146a-5p can be a marker for cellular senescence. This miRNA represents one of the significant SASP factors that if not precisely regulated, can accentuate inflammatory responses and stimulate senescence in surrounding non-senescent cells. The role of miR-146a-5p is different in healthy versus stressed cells, suggesting potential effects of this miRNA depend on overall organismal health, aging, and metabolic state.

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Funding

This work was supported by NIH grants R56 AG061414 (M.M.), R15 AG059190 (M.M), R03 AG059846 (M.M.), R21 AG062985 (M.M), R37AG13925 (JLK, TT) PO1 AG043376 (PDR), U19 AG056278 (PDR), and PO1AG062413 (JLK, TT, PDR). JLK and TT are also supported by the Connor Fund, Robert J. and Theresa W. Ryan, and the Noaber Foundation. A portion of this work was supported by NASA-Florida Space Grant Consortium, 66016A30 grant “Biomanufacturing of Vascularized Tissues”, and by the NASA (SSERVI16) Cooperative Agreement (NNH16ZDA001N) program titled “Radiation Effects on Volatiles and Exploration of Asteroids and Lunar Surfaces (REVEALS)”, 80ARC017M0007.

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Authors and Affiliations

  1. Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, 32827, USA

    Allancer D. C. Nunes, Sarah Noureddine, Lin Yu, Collin Lahde & Michal M. Masternak

  2. Institute On the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, 55455, USA

    Allancer D. C. Nunes & Paul D. Robbins

  3. Ludwig Boltzmann Institute of Traumatology in Cooperation With AUVA, Vienna, Austria

    Moritz Weigl & Johannes Grillari

  4. Faculdade de Nutrição, Universidade Federal de Pelotas, Pelotas, Brazil

    Augusto Schneider

  5. Centro de Desenvolvimento Tecnológico, Universidade Federal de Pelotas, Pelotas, Brazil

    Tatiana Dandolini Saccon

  6. Biomedical Engineering, Florida Tech, Melbourne, FL, 32901, USA

    Kunal Mitra

  7. Florida Space Institute, University of Central Florida, Orlando, FL, 32826, USA

    Esther Beltran

  8. Institute of Molecular Biotechnology, BOKU–University of Natural Resources and Life Sciences, Vienna, Austria

    Johannes Grillari

  9. Robert and Arlene Kogod Center On Aging, Mayo Clinic, Rochester, MN, 55905, USA

    James L. Kirkland & Tamara Tchkonia

  10. Department of Head and Neck Surgery, Poznan University of Medical Sciences, Poznan, Poland

    Michal M. Masternak

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  1. Allancer D. C. Nunes
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Nunes, A.D.C., Weigl, M., Schneider, A. et al. miR-146a-5p modulates cellular senescence and apoptosis in visceral adipose tissue of long-lived Ames dwarf mice and in cultured pre-adipocytes. GeroScience 44, 503–518 (2022). https://doi.org/10.1007/s11357-021-00490-3

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