The adaptive antioxidant response during fasting-induced muscle atrophy is oppositely regulated by ZEB1 and ZEB2.

Autor: Ninfali C; Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, Institute of Biomedical Research August Pi Sunyer (IDIBAPS), Barcelona 08036, Spain., Cortés M; Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, Institute of Biomedical Research August Pi Sunyer (IDIBAPS), Barcelona 08036, Spain., Martínez-Campanario MC; Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, Institute of Biomedical Research August Pi Sunyer (IDIBAPS), Barcelona 08036, Spain., Domínguez V; National Center of Biotechnology (CSIC-CNB) and Center for Molecular Biology Severo Ochoa (CSIC-CBMSO), Transgenesis Facility, High Research Council (CSIC) and Autonomous University of Madrid, Cantoblanco, Madrid 28049, Spain., Han L; Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, Institute of Biomedical Research August Pi Sunyer (IDIBAPS), Barcelona 08036, Spain., Tobías E; Group of Muscle Research and Mitochondrial Function, Institute of Biomedical Research August Pi Sunyer (IDIBAPS), University of Barcelona School of Medicine, Hospital Clínic of Barcelona, and Rare Diseases Networking Biomedical Research Center (CIBERer), Barcelona 08036, Spain., Esteve-Codina A; National Center for Genomics Analysis (CNAG), Barcelona 08028, Spain., Enrich C; Department of Biomedicine, University of Barcelona School of Medicine, and Institute of Biomedical Research August Pi Sunyer (IDIBAPS), Barcelona 08036, Spain., Pintado B; National Center of Biotechnology (CSIC-CNB) and Center for Molecular Biology Severo Ochoa (CSIC-CBMSO), Transgenesis Facility, High Research Council (CSIC) and Autonomous University of Madrid, Cantoblanco, Madrid 28049, Spain., Garrabou G; Group of Muscle Research and Mitochondrial Function, Institute of Biomedical Research August Pi Sunyer (IDIBAPS), University of Barcelona School of Medicine, Hospital Clínic of Barcelona, and Rare Diseases Networking Biomedical Research Center (CIBERer), Barcelona 08036, Spain., Postigo A; Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, Institute of Biomedical Research August Pi Sunyer (IDIBAPS), Barcelona 08036, Spain.; Molecular Targets Program, Department of Medicine, James Graham Brown Cancer Center, Louisville, KY 40202.; Catalan Institution for Research and Advanced Studies (ICREA), Barcelona 08010, Spain.
Jazyk: angličtina
Zdroj: Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2023 Nov 14; Vol. 120 (46), pp. e2301120120. Date of Electronic Publication: 2023 Nov 10.
DOI: 10.1073/pnas.2301120120
Abstrakt: Reactive oxygen species (ROS) serve important homeostatic functions but must be constantly neutralized by an adaptive antioxidant response to prevent supraphysiological levels of ROS from causing oxidative damage to cellular components. Here, we report that the cellular plasticity transcription factors ZEB1 and ZEB2 modulate in opposing directions the adaptive antioxidant response to fasting in skeletal muscle. Using transgenic mice in which Zeb1 or Zeb2 were specifically deleted in skeletal myofibers, we show that in fasted mice, the deletion of Zeb1 , but not Zeb2 , increased ROS production and that the adaptive antioxidant response to fasting essentially requires ZEB1 and is inhibited by ZEB2. ZEB1 expression increased in fasted muscles and protected them from atrophy; conversely, ZEB2 expression in muscles decreased during fasting and exacerbated muscle atrophy. In fasted muscles, ZEB1 reduces mitochondrial damage and increases mitochondrial respiratory activity; meanwhile, ZEB2 did the opposite. Treatment of fasting mice with Zeb1 -deficient myofibers with the antioxidant triterpenoid 1[2-cyano-3,12-dioxool-eana-1,9(11)-dien-28-oyl] trifluoro-ethylamide (CDDO-TFEA) completely reversed their altered phenotype to that observed in fasted control mice. These results set ZEB factors as potential therapeutic targets to modulate the adaptive antioxidant response in physiopathological conditions and diseases caused by redox imbalance.
Databáze: MEDLINE
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