title: Disruption of nuclear factor (erythroid-derived-2)-like 2 antioxidant signaling: a mechanism for impaired activation of stem cells and delayed regeneration of skeletal muscle.
abstract: Recently we have reported that age-dependent decline in antioxidant levels accelerated apoptosis and skeletal muscle degeneration. Here, we demonstrate genetic ablation of the master cytoprotective transcription factor, nuclear factor (erythroid-derived-2)-like 2 (Nrf2), aggravates cardiotoxin (CTX)-induced tibialis anterior (TA) muscle damage. Disruption of Nrf2 signaling sustained the CTX-induced burden of reactive oxygen species together with compromised expression of antioxidant genes and proteins. Transcript/protein expression of phenotypic markers of muscle differentiation, namely paired box 7 (satellite cell) and early myogenic differentiation and terminal differentiation (myogenin and myosin heavy chain 2) were increased on d 2 and 4 postinjury but later returned to baseline levels on d 8 and 15 in wild-type (WT) mice. In contrast, these responses were persistently augmented in Nrf2-null mice suggesting that regulation of the regeneration-related signaling mechanisms require Nrf2 for normal functioning. Furthermore, Nrf2-null mice displayed slower regeneration marked by dysregulation of embryonic myosin heavy chain temporal expression. Histologic observations illustrated that Nrf2-null mice displayed smaller, immature TA muscle fibers compared with WT counterparts on d 15 after CTX injury. Improvement in TA muscle morphology and gain in muscle mass evident in the WT mice was not noticeable in the Nrf2-null animals. Taken together these data show that the satellite cell activation, proliferation, and differentiation requires a functional Nrf2 system for effective healing following injury.-Shelar, S. B., Narasimhan, M., Shanmugam, G., Litovsky, S. H., Gounder, S. S., Karan, G., Arulvasu, C., Kensler, T. W., Hoidal, J. R., Darley-Usmar, V. M., Rajasekaran, N. S. Disruption of nuclear factor (erythroid-derived-2)-like 2 antioxidant signaling: a mechanism for impaired activation of stem cells and delayed regeneration of skeletal muscle.
authors.affiliation: Cardiac Aging and Redox Signaling Laboratory, Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA;
authors.forename: Sandeep Balu
authors.initials: SB
authors.lastname: Shelar
authors.affiliation: Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, Texas, USA;
authors.forename: Madhusudhanan
authors.initials: M
authors.lastname: Narasimhan
authors.affiliation: Cardiac Aging and Redox Signaling Laboratory, Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA;
authors.forename: Gobinath
authors.initials: G
authors.lastname: Shanmugam
authors.affiliation: Division of Anatomic Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA;
authors.forename: Silvio Hector
authors.initials: SH
authors.lastname: Litovsky
authors.affiliation: Division of Cardiovascular Medicine/Pulmonary Medicine, Department of Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA;
authors.forename: Sellamuthu S
authors.initials: SS
authors.lastname: Gounder
authors.affiliation: Mirx Pharmaceuticals, Lexington, Kentucky, USA;
authors.forename: Goutam
authors.initials: G
authors.lastname: Karan
authors.affiliation: Department of Zoology, University of Madras, Chennai, India; and.
authors.forename: Cinnasamy
authors.initials: C
authors.lastname: Arulvasu
authors.affiliation: Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Kensler
authors.affiliation: Division of Cardiovascular Medicine/Pulmonary Medicine, Department of Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA;
authors.forename: John R
authors.initials: JR
authors.lastname: Hoidal
authors.affiliation: Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA;
authors.forename: Victor M
authors.initials: VM
authors.lastname: Darley-Usmar
authors.affiliation: Cardiac Aging and Redox Signaling Laboratory, Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA; Division of Cardiovascular Medicine/Pulmonary Medicine, Department of Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA; Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA; rajnsr@uab.edu.
authors.forename: Namakkal S
authors.initials: NS
authors.lastname: Rajasekaran
mesh_terms: D000375:Aging; D000818:Animals; D000975:Antioxidants / Q000502:physiology*; D054715:Cardiotoxins / Q000633:toxicity*; D002460:Cell Line; D049109:Cell Proliferation / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000254:growth & development*; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D012038:Regeneration / Q000502:physiology; D032496:Satellite Cells, Skeletal Muscle / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013234:Stem Cells
chemical_list: D000975:Antioxidants; D054715:Cardiotoxins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human
keywords: Nrf2/ARE; Pax7; TA muscle; cardiotoxin; satellite cell
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