A Zeb1/Mitochondrial Creatine Kinase Metabolic Axis Controls Osteoclast Activation and Skeletal Remodeling
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ABSTRACT:
PROVIDER: PRJNA874930 | ENA |
REPOSITORIES: ENA
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Project description:To begin identifying potential Zeb1 targets capable of regulating bone resorbing activity, we conducted a transcriptome analysis comparing the expression profiles of wild-type versus Zeb1ΔM/ΔM osteoclasts.
2023-01-27 | GSE212302 | GEO
Project description:Osteoclasts are bone-resorbing polykaryons responsible for skeletal remodeling during health and disease. Coincident with their differentiation from myeloid precursors, osteoclasts undergo extensive transcriptional and metabolic reprogramming in order to acquire the cellular machinery necessary to demineralize bone and digest its interwoven extracellular matrix. While attempting to identify new regulatory molecules critical to bone resorption, we discovered that murine and human osteoclast differentiation is accompanied by the expression of Zeb1, a zinc-finger transcriptional repressor whose role in normal development is most frequently linked to the control of epithelial-mesenchymal programs. However, following targeting, we find that Zeb1 serves as an unexpected regulator of osteoclast energy metabolism. In vivo, Zeb1-null osteoclasts assume a hyperactivated state, markedly decreasing bone density due to excessive resorptive activity. Mechanistically, Zeb1 acts in a rheostat-like fashion to modulate murine and human osteoclast activity by transcriptionally repressing an ATP-buffering enzyme, mitochondrial creatine kinase 1 (MtCK1), thereby controlling the phosphocreatine energy shuttle and mitochondrial respiration. Together, these studies identify a novel Zeb1/MtCK1 axis that exerts metabolic control over bone resorption in vitro and in vivo.
| S-EPMC10068323 | biostudies-literature
Project description:Osteoclasts are bone-resorbing polykaryons responsible for skeletal remodeling during health and disease. Coincident with their differentiation from myeloid precursors, osteoclasts undergo extensive transcriptional and metabolic reprogramming in order to acquire the cellular machinery necessary to demineralize bone and digest its interwoven extracellular matrix. While attempting to identify new regulatory molecules critical to bone resorption, we discovered that murine and human osteoclast differentiation is accompanied by the expression of Zeb1, a zinc-finger transcriptional repressor whose role in normal development is most frequently linked to the control of epithelial-mesenchymal programs. However, following targeting, we find that Zeb1 serves as an unexpected regulator of osteoclast energy metabolism. In vivo, Zeb1-null osteoclasts assume a hyperactivated state, markedly decreasing bone density due to excessive resorptive activity. Mechanistically, Zeb1 acts in a rheostat-like fashion to modulate murine and human osteoclast activity by transcriptionally repressing an ATP-buffering enzyme, mitochondrial creatine kinase 1 (MtCK1), thereby controlling the phosphocreatine energy shuttle and mitochondrial respiration. Together, these studies identify a novel Zeb1/MtCK1 axis that exerts metabolic control over bone resorption in vitro and in vivo.
| S-SCDT-10_15252-EMBJ_2022111148 | biostudies-other
Project description:Expression profiling of vastus lateralis muscle of young, healthy, non-obese men supplemented with creatine monohydrate vs. placebo for 10 days. Results identify transcriptional pathways activated in skeletal muscles as a result of acute creatine monohydrate supplementation. Keywords: Supplementation response.
2007-05-23 | GSE7877 | GEO
Project description:Expression profiling of vastus lateralis muscle of young, healthy, non-obese men supplemented with creatine monohydrate vs. placebo for 10 days. Results identify transcriptional pathways activated in skeletal muscles as a result of acute creatine monohydrate supplementation. Keywords: Supplementation response. In a randomized, placebo-controlled, crossover, double-blind design, 12 young, healthy, non-obese men were supplemented with either a placebo or creatine monohydrate (loading phase, 20 g/d x 3 d; maintenance phase, 5 g/d x 7 d) for 10 d. Following a 28 day washout period, subjects were put on the alternate supplementation for 10 days. Muscle biopsies of the vastus lateralis were obtained and were assessed for global mRNA expression using cDNA microarrays.
2010-06-11 | E-GEOD-7877 | biostudies-arrayexpress
Project description:diaPASEF based proteomic analysis of a murine model with a CRISPR knockout of creatine kinase brain type to determine the effects of this protein in limiting tenofovir prodrug activation. File names include the animal number, sex and technical replicate number, along with the organ analyzed. Complete metadata will be provided in the publication preprint.
2023-05-17 | MSV000091978 | MassIVE
Project description:The mechanisms promoting disturbed white adipocyte function in obesity remain largely unclear. Herein, we integrate white adipose tissue (WAT) metabolomic and transcriptomic data from clinical cohorts and find that the WAT phosphocreatine/creatine ratio is increased and creatine kinase-B expression and activity is decreased in the obese state. . In human in vitro and murine in vivo models, we demonstrate that decreased phosphocreatine metabolism in white adipocytes alters AMPK activity via effects on ATP/ADP levels, independently of WAT beigeing. This disturbance promotes a pro-inflammatory profile characterized, in part, by increased CCL2 production. These data suggest that the phosphocreatine/creatine system links cellular energy shuttling with pro-inflammatory responses in human and murine white adipocytes. Our findings provide unexpected perspectives on the mechanisms driving WAT inflammation in obesity and may present avenues to target adipocyte dysfunction.
2022-01-27 | GSE192361 | GEO
Project description:Noradrenaline regulates cold-stimulated adipocyte thermogenesis. Aside from cAMP signaling downstream of β-adrenergic receptor (βAR) activation, how noradrenaline promotes thermogenic output is still not fully understood. Here, we show that coordinated α1-adrenergic receptor (α1AR) and β3AR signaling induces the expression of thermogenic genes of the futile creatine cycle, and that EBFs, ERRs, and PGC1α are required for this response in vivo. Noradrenaline triggers physical and functional coupling between the α1AR subtype (ADRA1A) to Gαq to promote adipocyte thermogenesis in a manner that is dependent on the effector proteins of the futile creatine cycle, creatine kinase b (CKB) and tissue-nonspecific alkaline phosphatase (TNAP). Combined Gαq and Gαs signaling selectively in adipocytes promotes a continual rise in whole-body energy expenditure, and CKB is required for this effect. Thus, the ADRA1A-Gαq-futile creatine cycle axis is a key regulator of facultative and adaptive thermogenesis.
2022-09-08 | GSE207340 | GEO
Project description:Noradrenaline regulates cold-stimulated adipocyte thermogenesis. Aside from cAMP signaling downstream of β-adrenergic receptor (βAR) activation, how noradrenaline promotes thermogenic output is still not fully understood. Here, we show that coordinated α1-adrenergic receptor (α1AR) and β3AR signaling induces the expression of thermogenic genes of the futile creatine cycle, and that EBFs, ERRs, and PGC1α are required for this response in vivo. Noradrenaline triggers physical and functional coupling between the α1AR subtype (ADRA1A) to Gαq to promote adipocyte thermogenesis in a manner that is dependent on the effector proteins of the futile creatine cycle, creatine kinase b (CKB) and tissue-nonspecific alkaline phosphatase (TNAP). Combined Gαq and Gαs signaling selectively in adipocytes promotes a continual rise in whole-body energy expenditure, and CKB is required for this effect. Thus, the ADRA1A-Gαq-futile creatine cycle axis is a key regulator of facultative and adaptive thermogenesis.
2022-09-08 | GSE207341 | GEO
Project description:We found that the creatine metabolic pathway was differentially regulated under M1 versus M2 polarizing conditions. In return, creatine could suppress M1 by blocking STAT1 tyrosine phosphorylation while promote M2 by sustaining chromatin accessibility of specific gene loci.
2019-08-06 | GSE110403 | GEO