Evidence of Notch-Hesr-Nrf2 Axis in Muscle Stem Cells, but Absence of Nrf2 Has No Effect on Their Quiescent and Undifferentiated State

Masahiko Yamaguchi; Satoshi Murakami; Tomohiro Yoneda; Miki Nakamura; Lidan Zhang; Akiyoshi Uezumi; Sumiaki Fukuda; Hiroki Kokubo; Kazutake Tsujikawa; So-Ichiro Fukada

doi:10.1371/journal.pone.0138517

Evidence of Notch-Hesr-Nrf2 Axis in Muscle Stem Cells, but Absence of Nrf2 Has No Effect on Their Quiescent and Undifferentiated State

PLoS One. 2015 Sep 29;10(9):e0138517. doi: 10.1371/journal.pone.0138517. eCollection 2015.

Affiliations

¹ Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
² Division for Therapies Against Intractable Diseases, Institute for Comprehensive Medical Science, Fujita Health University, 1-98 Dengakugakubo, Kutsukake, Toyoake, Aichi 470-1192, Japan.
³ Department of Cardiovascular Physiology and Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minamiku, Hiroshima 734-8551, Japan.

Abstract

Nrf2 is a master regulator of oxidative stresses through the induction of anti-oxidative genes. Nrf2 plays roles in maintaining murine hematopoietic stem cells and fly intestinal stem cells. The canonical Notch signaling pathway is also crucial for maintaining several types of adult stem cells including muscle stem cells (satellite cells). Here, we show that Dll1 induced Nrf2 expression in myogenic cells. In addition, primary targets of Notch signaling, Hesr1 and Hesr3, were involved in the up-regulation of Nrf2 mRNA and expression of its target genes. In vitro, Nrf2 had anti-myogenic and anti-proliferative effects on primary myoblasts. In vivo, although Nrf2-knockout mice showed decreased expression of its target genes in muscle stem cells, adult muscle stem cells of Nrf2-knockout mice did not exhibit the phenotype. Taken together, in muscle stem cells, the Notch-Hesr-Nrf2 axis is a pathway potentially inducing anti-oxidative genes, but muscle stem cells either do not require Nrf2-mediated anti-oxidative gene expression or they have a complementary system compensating for the loss of Nrf2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult Stem Cells / cytology
Animals
Antioxidants / metabolism
Basic Helix-Loop-Helix Transcription Factors / genetics*
Basic Helix-Loop-Helix Transcription Factors / metabolism
CHO Cells
Calcium-Binding Proteins
Cell Cycle Proteins / genetics*
Cell Cycle Proteins / metabolism
Cell Differentiation / genetics
Cell Line
Cricetulus
Intercellular Signaling Peptides and Proteins / metabolism
Mice
Mice, Knockout
Muscle Cells / cytology
Muscle Cells / metabolism
Muscle Development / genetics
NF-E2-Related Factor 2 / genetics*
NF-E2-Related Factor 2 / metabolism
Receptors, Notch / metabolism*
Satellite Cells, Skeletal Muscle / cytology*
Satellite Cells, Skeletal Muscle / metabolism
Signal Transduction

Substances

Antioxidants
Basic Helix-Loop-Helix Transcription Factors
Calcium-Binding Proteins
Cell Cycle Proteins
Dlk1 protein, mouse
Hey1 protein, mouse
Heyl protein, mouse
Intercellular Signaling Peptides and Proteins
NF-E2-Related Factor 2
Nfe2l2 protein, mouse
Receptors, Notch

Grants and funding

This work was supported by a JSPS KAKENHI grant, Grant-in Aid for Young Scientists (A) (25702044 to So-ichiro F), Intramural Research Grant (22-5 to So-ichiro F, 25-5 to So-ichiro F) for Neurological and Psychiatric Disorders of NCNP (NationalCenter of Neurology and Psychiatry), and The Nakatomi Foundation (to So-ichiro F).