Cells
·
2021
·Vol. 10
·期 2
·237
·
IF 6.6
Guobin Li,Lan Zhang,Kaiting Ning,Baoqiang Yang,Francisca M. Acosta,Peng Shang,Jean X. Jiang,Huiyun Xu
Bone–muscle crosstalk plays an important role in skeletal biomechanical function, the progression of numerous pathological conditions, and the modulation of local and distant cellular environments. Previous work has revealed that the deletion of connexin (Cx) 43 in osteoblasts, and consequently, osteocytes, indirectly compromises skeletal muscle formation and function. However, the respective roles of Cx43-formed gap junction channels (GJs) and hemichannels (HCs) in the bone–muscle crosstalk are poorly understood. To this end, we used two Cx43 osteocyte-specific transgenic mouse models expressing dominant negative mutants, Δ130–136 (GJs and HCs functions are inhibited), and R76W (only GJs function is blocked), to determine the effect of these two types of Cx43 channels on neighboring skeletal muscle. Blockage of osteocyte Cx43 GJs and HCs in Δ130–136 mice decreased fast-twitch muscle mass with reduced muscle protein synthesis and increased muscle protein degradation. Both R76W and Δ130–136 mice exhibited decreased muscle contractile force accompanied by a fast-to-slow fiber transition in typically fast-twitch muscles. In vitro results further showed that myotube formation of C2C12 myoblasts was inhibited after treatment with the primary osteocyte conditioned media (PO CM) from R76W and Δ130–136 mice. Additionally, prostaglandin E2 (PGE2) level was significantly reduced in both the circulation and PO CM of the transgenic mice. Interestingly, the injection of PGE2 to the transgenic mice rescued fast-twitch muscle mass and function; however, this had little effect on protein synthesis and degradation. These findings indicate a channel-specific response: inhibition of osteocytic Cx43 HCs decreases fast-twitch skeletal muscle mass alongside reduced protein synthesis and increased protein degradation. In contrast, blockage of Cx43 GJs results in decreased fast-twitch skeletal muscle contractile force and myogenesis, with PGE2 partially accounting for the measured differences.Keywords:osteocytes;Cx43;gap junctions;hemichannels;bone–muscle crosstalk
研究领域:
生物力学
·
分子生物学
·
生理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
LIFE SCIENCES
·
2025
·
IF 5.1
Zexuan Li,Xinyue Deng,Yanna Cao,Hongbo Xu,Jiangang Wang,Lamei Yuan,Hao Deng
Aim Congenital cataract, a lenticular opacity diagnosed at birth or early in the postnatal period, often causes visual impairment. The pathogenic mechanisms of various cataract-associated variants are complex and diverse, and current knowledge is insufficient. This study aimed to determine the molecular etiology of congenital nuclear cataract in a Han-Chinese family and to reveal the pathogenic mechanisms of common cataract-associated variants with unclear mechanisms. Methods Genetic analysis including whole exome sequencing and bioinformatics was conducted in the family. Functional analysis was performed to elucidate the changes in protein cellular distribution, degradation, and function induced by the variants. Results A heterozygous c.773C > T transition (p.S258F) in the gap junction protein alpha 8 gene ( GJA8 ), encoding connexin 50 (Cx50), was identified in a family with congenital nuclear cataract. Functional analysis of this variant and two other GJA8 variants with unclear pathogenic mechanisms showed that the Cx50V44M mutant correctly trafficked to the plasma membrane, whereas the Cx50R76C mutant and Cx50S258F mutant exhibited trafficking defects resulting from delayed degradation and accelerated degradation, respectively. All three mutants exhibited increased autophagic activity, while only the Cx50V44M mutant and Cx50S258F mutant underwent autophagy-mediated Cx50 degradation. All mutants failed to form functional hemichannels and gap junction channels. Significance This study identified a heterozygous GJA8 missense variant c.773C > T (p.S258F) responsible for congenital nuclear cataract, and revealed three distinct pathogenic mechanisms of three cataract-associated GJA8 variants, particularly emphasizing dysregulated autophagy involving in aberrant Cx50 degradation.
研究领域:
医学遗传学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMOSPHERE
·
2023
·
IF 8.8
Jian Sun,Huayi Qu,Waseem Ali,Yan Chen,Tao Wang,Yonggang Ma,Yan Yuan,Jianhong Gu,Jianchun Bian,Zongping Liu,Hui Zou
Microplastics (MPs) and cadmium (Cd) are important environmental pollutants, that damage the liver. However, the effect and mechanism of combined Cd and MPs exposure on liver fibrosis are still largely unknown. In this study investigated, Cd + MPs exposure increased superoxide anion production and promoted extracellular ATP release compared with exposure to Cd or MPs individually. Cd + MPs increased inflammatory cell infiltration , activated the P2X7-NLRP3 signaling pathway, and promoted inflammatory factor release. Cd + MPs aggravated Cd- or MPs-induced liver fibrosis and induced liver inflammation. In AML12/HSC-T6 cell in vitro poisoning model, exposure of AML12 cells to Cd + MPs increased the opening of connexin hemichannels and promoted extracellular ATP release. Treatment of HSC-T6 cells with the supernatant of AML12 cells exposed to Cd + MPs significantly promoted HSC-T6 cell activation. Treatment of HSC-T6 cells with different concentrations of ATP produced similar results. TAT-Gap19TFA, an inhibitor of connexin hemichannels, significantly inhibited the ATP release and activation of Cd + MPs-treated HSC-T6 cells. Finally, the expression of the ATP receptor P2X7 was silenced in HSC-T6 cells, which significantly inhibited their activation. In conclusion, exposure to Cd + MPs promoted liver fibrosis through the ATP-P2X7 pathway and synergistically affected liver inflammation and fibrosis.
研究领域:
环境科学
·
毒理学
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Science Signaling
·
2020
·Vol. 13
·期 646
·
IF 6.467
Xiao-Wei Gu,Zi-Cong Chen,Zhen-Shan Yang,Yan Yang,Ya-Ping Yan,Yue-Fang Liu,Ji-Min Pan,Ren-Wei Su,Zeng-Ming Yang
Embryo implantation involves a sterile inflammatory reaction that is required for the invasion of the blastocyst into the decidua. Adenosine triphosphate (ATP) released from stressed or injured cells acts as an important signaling molecule to regulate many key physiological events, including sterile inflammation. We found that the amount of ATP in the uterine luminal fluid of mice increased during the peri-implantation period, and this depended on the presence of an embryo. We further showed that the release of ATP from receptive epithelial cells was likely stimulated by lactate released from the blastocyst through connexin hemichannels. The ATP receptor P2y2 was present on uterine epithelial cells during the preimplantation period and increased in the stromal cells during the time at which decidualization began. Pharmacological inhibition of P2y2 compromised decidualization and implantation. ATP-P2y2 signaling stimulated the phosphorylation of Stat3 in uterine luminal epithelial cells and the expression of early growth response 1 ( Egr1 ) and prostaglandin-endoperoxide synthase 2 ( Ptgs2, also known as Cox-2 ), all of which are required for decidualization and/or implantation, in stromal cells. Short exposure to high concentrations of ATP promoted decidualization of primary stromal cells, but longer exposures or lower ATP concentrations did not. The expression of genes encoding ATP-degrading ectonucleotidases increased in the decidua during the peri-implantation period, suggesting that they may limit the duration of the ATP signal. Together, our results indicate that the blastocyst-induced release of ATP from uterine epithelial cells during the peri-implantation period may be important for the initiation of stromal cell decidualization.
研究领域:
生殖生物学
·
发育生物学
·
细胞信号转导
·
分子胚胎学
·
免疫学（无菌性炎症）
✓ 已验证
DOI
高影响因子
危险品化学品经营许可证（带存储）