title: Nrf2 deficiency promotes apoptosis and impairs PAX7/MyoD expression in aging skeletal muscle cells.
abstract: Skeletal muscle redox homeostasis is transcriptionally regulated by nuclear erythroid-2-p45-related factor-2 (Nrf2). We recently demonstrated that age-associated stress impairs Nrf2-ARE (antioxidant-response element) transcriptional signaling. Here, we hypothesize that age-dependent decline or genetic ablation of Nrf2 leads to accelerated apoptosis and skeletal muscle degeneration. Under basal-physiological conditions, disruption of Nrf2 significantly downregulates antioxidants and causes oxidative stress. Surprisingly, Nrf2-null mice had enhanced antioxidant capacity identical to wild-type (WT) upon acute endurance exercise stress (AEES), suggesting activation of Nrf2-independent mechanisms (i.e., PGC1α) against oxidative stress. Analysis of prosurvival pathways in the basal state reveals decreased AKT levels, whereas p-p53, a repressor of AKT, was increased in Nrf2-null vs WT mice. Upon AEES, AKT and p-AKT levels were significantly (p < 0.001) increased (>10-fold) along with profound downregulation of p-p53 (p < 0.01) in Nrf2-null vs WT skeletal muscle, indicating the onset of prosurvival mechanisms to compensate for the loss of Nrf2 signaling. However, we found a decreased stem cell population (PAX7) and MyoD expression (differentiation) along with profound activation of ubiquitin and apoptotic pathways in Nrf2-null vs WT mice upon AEES, suggesting that compensatory prosurvival mechanisms failed to overcome the programmed cell death and degeneration in skeletal muscle. Further, the impaired regeneration was sustained in Nrf2-null vs WT mice after 1 week of post-AEES recovery. In an age-associated oxidative stress condition, ablation of Nrf2 results in induction of apoptosis and impaired muscle regeneration.
authors.affiliation: Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Cardiac Aging and Redox Signaling Laboratory, Division of Cardiology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
authors.forename: Madhusudhanan
authors.initials: M
authors.lastname: Narasimhan
authors.affiliation: Cardiac Aging and Redox Signaling Laboratory, Division of Cardiology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hong
authors.affiliation: Cardiac Aging and Redox Signaling Laboratory, Division of Cardiology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Atieno
authors.affiliation: Cardiac Aging and Redox Signaling Laboratory, Division of Cardiology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
authors.forename: Vasanthi R
authors.initials: VR
authors.lastname: Muthusamy
authors.affiliation: Cardiac Aging and Redox Signaling Laboratory, Division of Cardiology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Davidson
authors.affiliation: Cardiac Aging and Redox Signaling Laboratory, Division of Cardiology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
authors.forename: Naser
authors.initials: N
authors.lastname: Abu-Rmaileh
authors.affiliation: Division of Geriatrics, and Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132, USA; Department of Exercise & Sports Sciences, College of Health, University of Utah, Salt Lake City, UT 84112, USA; Geriatric Research, Education, and Clinical Center, Salt Lake City Veteran's Medical Center.
authors.forename: Russell S
authors.initials: RS
authors.lastname: Richardson
authors.affiliation: University of California at Davis, Davis, CA 95616, USA.
authors.forename: Aldrin V
authors.initials: AV
authors.lastname: Gomes
authors.affiliation: Division of Pulmonary Medicine, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Hoidal
authors.affiliation: Cardiac Aging and Redox Signaling Laboratory, Division of Cardiology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132, USA; Department of Exercise & Sports Sciences, College of Health, University of Utah, Salt Lake City, UT 84112, USA. Electronic address: Raj.Soorappan@hsc.utah.edu.
authors.forename: Namakkal S
authors.initials: NS
authors.lastname: Rajasekaran
mesh_terms: D000375:Aging / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D061745:Antioxidant Response Elements; D017209:Apoptosis; D017079:Exercise Tolerance / Q000235:genetics; D005786:Gene Expression Regulation; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D017570:MyoD Protein / Q000235:genetics* / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000172:deficiency / Q000235:genetics*; D018384:Oxidative Stress; D051763:PAX7 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism
chemical_list: D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D051763:PAX7 Transcription Factor; C497322:Pax7 protein, mouse; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; D051057:Proto-Oncogene Proteins c-akt
keywords: Aging; Free radicals; Nrf2; PAX7/MyoD; Skeletal muscle; Stem cells