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DNA repair byproduct 8-oxoguanine base promotes myoblast differentiation.

ABSTRACT: Muscle contraction increases the level of reactive oxygen species (ROS), which has been acknowledged as key signaling entities in muscle remodeling and to underlie the healthy adaptation of skeletal muscle. ROS inevitably endows damage to various cellular molecules including DNA. DNA damage ought to be repaired to ensure genome integrity; yet, how DNA repair byproducts affect muscle adaptation remains elusive. Here, we showed that exercise elicited the generation of 8-oxo-7,8-dihydroguanine (8-oxoG), that was primarily found in mitochondrial genome of myofibers. Upon exercise, TA muscle's 8-oxoG excision capacity markedly enhanced, and in the interstitial fluid of TA muscle from the post-exercise mice, the level of free 8-oxoG base was significantly increased. Addition of 8-oxoG to myoblasts triggered myogenic differentiation via activating Ras-MEK-MyoD signal axis. 8-Oxoguanine DNA glycosylase1 (OGG1) silencing from cells or Ogg1 KO from mice decreased Ras activation, ERK phosphorylation, MyoD transcriptional activation, myogenic regulatory factors gene (MRFs) expression. In reconstruction experiments, exogenously added 8-oxoG base enhanced the expression of MRFs and accelerated the recovery of the injured skeletal muscle. Collectively, these data not only suggest that DNA repair metabolite 8-oxoG function as a signal entity for muscle remodeling and contribute to exercise-induced adaptation of skeletal muscle, but also raised the potential for utilizing 8-oxoG in clinical treatment to skeletal muscle damage-related disorders.

SUBMITTER: Zheng X

PROVIDER: S-EPMC9982643 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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DNA repair byproduct 8-oxoguanine base promotes myoblast differentiation.

Zheng Xu X Zhang Wenhe W Hu Yinchao Y Zhao Zhexuan Z Wu Jiaxin J Zhang Xiaoqing X Hao Fengqi F Han Jinling J Xu Jing J Hao Wenjing W Wang Ruoxi R Tian Meihong M Radak Zsolt Z Nakabeppu Yusaku Y Boldogh Istvan I Ba Xueqing X

Redox biology 20230215

Muscle contraction increases the level of reactive oxygen species (ROS), which has been acknowledged as key signaling entities in muscle remodeling and to underlie the healthy adaptation of skeletal muscle. ROS inevitably endows damage to various cellular molecules including DNA. DNA damage ought to be repaired to ensure genome integrity; yet, how DNA repair byproducts affect muscle adaptation remains elusive. Here, we showed that exercise elicited the generation of 8-oxo-7,8-dihydroguanine (8-o ...[more]

PMID: 36827746

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Project description:A growing body of evidence suggests that elevated levels of reactive oxygen species (ROS) in the airways caused by exposure to gas phase pollutants or particulate matter are able to activate dendritic cells (DCs); however, the exact mechanisms are still unclear. When present in excess, ROS can modify macromolecules including DNA. One of the most abundant DNA base lesions is 7,8-dihydro-8-oxoguanine (8-oxoG), which is repaired by the 8-oxoguanine DNA glycosylase 1 (OGG1)-initiated base excision repair (BER) (OGG1-BER) pathway. Studies have also demonstrated that in addition to its role in repairing oxidized purines, OGG1 has guanine nucleotide exchange factor activity when bound to 8-oxoG. In the present study, we tested the hypothesis that exposure to 8-oxoG, the specific product of OGG1-BER, induces functional changes of DCs. Supporting our hypothesis, transcriptome analysis revealed that in mouse lungs, out of 95 genes associated with DCs' function, 22 or 42 were significantly upregulated after a single or multiple intranasal 8-oxoG challenges, respectively. In a murine model of allergic airway inflammation, significantly increased serum levels of ovalbumin (OVA)-specific IgE antibodies were detected in mice sensitized via nasal challenges with OVA+8-oxoG compared to those challenged with OVA alone. Furthermore, exposure of primary human monocyte-derived DCs (moDC) to 8-oxoG base resulted in significantly enhanced expression of cell surface molecules (CD40, CD86, CD83, HLA-DQ) and augmented the secretion of pro-inflammatory mediators IL-6, TNF and IL-8, whereas it did not considerably influence the production of the anti-inflammatory cytokine IL-10. The stimulatory effects of 8-oxoG on human moDCs were abolished upon siRNA-mediated OGG1 depletion. Collectively, these data suggest that OGG1-BER-generated 8-oxoG base-driven cell signaling activates DCs, which may contribute to initiation of both the innate and adaptive immune responses under conditions of oxidative stress.

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DNA repair byproduct 8-oxoguanine base promotes myoblast differentiation.

Publications

DNA repair byproduct 8-oxoguanine base promotes myoblast differentiation.

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