7 research outputs found
Cardiosphere-derived cells demonstrate metabolic flexibility that Is influenced by adhesion status
Adult stem cells demonstrate metabolic flexibility that is regulated by cell adhesion status. The authors demonstrate that adherent cells primarily utilize glycolysis, whereas suspended cells rely on oxidative phosphorylation for their ATP needs. Akt phosphorylation transduces adhesion-mediated regulation of energy metabolism, by regulating translocation of glucose transporters (GLUT1) to the cell membrane and thus, cellular glucose uptake and glycolysis. Cell dissociation, a pre-requisite for cell transplantation, leads to energetic stress, which is mediated by Akt dephosphorylation, downregulation of glucose uptake, and glycolysis. They designed hydrogels that promote rapid cell adhesion of encapsulated cells, Akt phosphorylation, restore glycolysis, and cellular ATP levels
Differences in molecular phenotype in mouse and human hypertrophic cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is characterized by phenotypic
heterogeneity. We investigated the molecular basis of the cardiac
phenotype in two mouse models at established disease stage (mouse-HCM),
and human myectomy tissue (human-HCM). We analyzed the transcriptome in
2 mouse models with non-obstructive HCM (R403Q-MyHC,
R92W-TnT)/littermate-control hearts at 24 weeks of age, and in myectomy
tissue of patients with obstructive HCM/control hearts (GSE36961,
GSE36946). Additionally, we examined myocyte redox, cardiac
mitochondrial DNA copy number (mtDNA-CN), mt-respiration, mt-ROS
generation/scavenging and mt-Ca2+ handling in mice. We identified
distinct allele-specific gene expression in mouse-HCM, and marked
differences between mouse-HCM and human-HCM. Only two genes (CASQ1,
GPT1) were similarly dysregulated in both mutant mice and human-HCM. No
signaling pathway or transcription factor was predicted to be similarly
dysregulated (by Ingenuity Pathway Analysis) in both mutant mice and
human-HCM. Losartan was a predicted therapy only in TnT-mutant mice.
KEGG pathway analysis revealed enrichment for several metabolic
pathways, but only pyruvate metabolism was enriched in both mutant mice
and human-HCM. Both mutant mouse myocytes demonstrated evidence of an
oxidized redox environment. Mitochondrial complex I RCR was lower in
both mutant mice compared to controls. MyHC-mutant mice had similar
mtDNA-CN and mt-Ca2+ handling, but TnT-mutant mice exhibited lower
mtDNA-CN and impaired mt-Ca2+ handling, compared to littermate-controls.
Molecular profiling reveals differences in gene expression,
transcriptional regulation, intracellular signaling and
mt-number/function in 2 mouse models at established disease stage.
Further studies are needed to confirm differences in gene expression
between mouse and human-HCM, and to examine whether cardiac phenotype,
genotype and/or species differences underlie the divergence in molecular
profiles
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Allele-specific differences in transcriptome, miRNome, and mitochondrial function in two hypertrophic cardiomyopathy mouse models
Hypertrophic cardiomyopathy (HCM) stems from mutations in sarcomeric proteins that elicit distinct biophysical sequelae, which in turn may yield radically different intracellular signaling and molecular pathologic profiles. These signaling events remain largely unaddressed by clinical trials that have selected patients based on clinical HCM diagnosis, irrespective of genotype. In this study, we determined how two mouse models of HCM differ, with respect to cellular/mitochondrial function and molecular biosignatures, at an early stage of disease. We show that hearts from young R92W-TnT and R403Q-αMyHC mutation–bearing mice differ in their transcriptome, miRNome, intracellular redox environment, mitochondrial antioxidant defense mechanisms, and susceptibility to mitochondrial permeability transition pore opening. Pathway analysis of mRNA-sequencing data and microRNA profiles indicate that R92W-TnT mutants exhibit a biosignature consistent with activation of profibrotic TGF-β signaling. Our results suggest that the oxidative environment and mitochondrial impairment in young R92W-TnT mice promote activation of TGF-β signaling that foreshadows a pernicious phenotype in young individuals. Of the two mutations, R92W-TnT is more likely to benefit from anti–TGF-β signaling effects conferred by angiotensin receptor blockers and may be responsive to mitochondrial antioxidant strategies in the early stage of disease. Molecular and functional profiling may therefore serve as aids to guide precision therapy for HCM.John Taylor Babbitt (JTB) foundation; NIH grant [R01HL092985]; UCSF Division of Cardiology; American Heart Association [15SDG23220028]; National Institute of General Medical Sciences (NIGMS) [R01GM116841]; Johns Hopkins University Department of Biological Chemistry; Hellenic Cardiology Society; NIH Diversity Supplement; Wuxi Mei-Yuan Hospital, China; NIH [HL11738]This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]
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Allele-specific differences in transcriptome, miRNome, and mitochondrial function in two hypertrophic cardiomyopathy mouse models
Hypertrophic cardiomyopathy (HCM) stems from mutations in sarcomeric proteins that elicit distinct biophysical sequelae, which in turn may yield radically different intracellular signaling and molecular pathologic profiles. These signaling events remain largely unaddressed by clinical trials that have selected patients based on clinical HCM diagnosis, irrespective of genotype. In this study, we determined how two mouse models of HCM differ, with respect to cellular/mitochondrial function and molecular biosignatures, at an early stage of disease. We show that hearts from young R92W-TnT and R403Q-αMyHC mutation-bearing mice differ in their transcriptome, miRNome, intracellular redox environment, mitochondrial antioxidant defense mechanisms, and susceptibility to mitochondrial permeability transition pore opening. Pathway analysis of mRNA-sequencing data and microRNA profiles indicate that R92W-TnT mutants exhibit a biosignature consistent with activation of profibrotic TGF-β signaling. Our results suggest that the oxidative environment and mitochondrial impairment in young R92W-TnT mice promote activation of TGF-β signaling that foreshadows a pernicious phenotype in young individuals. Of the two mutations, R92W-TnT is more likely to benefit from anti-TGF-β signaling effects conferred by angiotensin receptor blockers and may be responsive to mitochondrial antioxidant strategies in the early stage of disease. Molecular and functional profiling may therefore serve as aids to guide precision therapy for HCM
Allele-specific differences in transcriptome, miRNome, and mitochondrial function in two hypertrophic cardiomyopathy mouse models
Hypertrophic cardiomyopathy (HCM) stems from mutations in sarcomeric proteins that elicit distinct biophysical sequelae, which in turn may yield radically different intracellular signaling and molecular pathologic profiles. These signaling events remain largely unaddressed by clinical trials that have selected patients based on clinical HCM diagnosis, irrespective of genotype. In this study, we determined how two mouse models of HCM differ, with respect to cellular/mitochondrial function and molecular biosignatures, at an early stage of disease. We show that hearts from young R92W-TnT and R403Q-αMyHC mutation–bearing mice differ in their transcriptome, miRNome, intracellular redox environment, mitochondrial antioxidant defense mechanisms, and susceptibility to mitochondrial permeability transition pore opening. Pathway analysis of mRNA-sequencing data and microRNA profiles indicate that R92W-TnT mutants exhibit a biosignature consistent with activation of profibrotic TGF-β signaling. Our results suggest that the oxidative environment and mitochondrial impairment in young R92W-TnT mice promote activation of TGF-β signaling that foreshadows a pernicious phenotype in young individuals. Of the two mutations, R92W-TnT is more likely to benefit from anti–TGF-β signaling effects conferred by angiotensin receptor blockers and may be responsive to mitochondrial antioxidant strategies in the early stage of disease. Molecular and functional profiling may therefore serve as aids to guide precision therapy for HCM.John Taylor Babbitt (JTB) foundation; NIH grant [R01HL092985]; UCSF Division of Cardiology; American Heart Association [15SDG23220028]; National Institute of General Medical Sciences (NIGMS) [R01GM116841]; Johns Hopkins University Department of Biological Chemistry; Hellenic Cardiology Society; NIH Diversity Supplement; Wuxi Mei-Yuan Hospital, China; NIH [HL11738]This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]
Cardiosphere-Derived Cells Demonstrate Metabolic Flexibility That Is Influenced by Adhesion Status
Adult stem cells demonstrate metabolic flexibility that is regulated by cell adhesion status. The authors demonstrate that adherent cells primarily utilize glycolysis, whereas suspended cells rely on oxidative phosphorylation for their ATP needs. Akt phosphorylation transduces adhesion-mediated regulation of energy metabolism, by regulating translocation of glucose transporters (GLUT1) to the cell membrane and thus, cellular glucose uptake and glycolysis. Cell dissociation, a pre-requisite for cell transplantation, leads to energetic stress, which is mediated by Akt dephosphorylation, downregulation of glucose uptake, and glycolysis. They designed hydrogels that promote rapid cell adhesion of encapsulated cells, Akt phosphorylation, restore glycolysis, and cellular ATP levels