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- 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.
- Authors
Shelar, Sandeep Balu; Narasimhan, Madhusudhanan; Shanmugam, Gobinath; Litovsky, Silvio Hector; Gounder, Sellamuthu S.; Karan, Goutam; Arulvasu, Cinnasamy; Kensler, Thomas W.; Hoidal, John R.; Darley-Usmar, Victor M.; Rajasekaran, Namakkal S.
- 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.
- Subjects
PHYSIOLOGICAL effects of antioxidants; CELLULAR signal transduction; SKELETAL muscle physiology; STEM cells; REGENERATION (Biology); AGE factors in disease
- Publication
FASEB Journal, 2016, Vol 30, Issue 5, p1865
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fj.201500153