E-PROT-91
Ontology highlight
ABSTRACT:
PROVIDER: E-PROT-91 | ExpressionAtlas | 2022-01-10
REPOSITORIES: ExpressionAtlas
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Project description:The human heart is capable of functioning for decades despite minimal cell turnover or regeneration, suggesting that molecular alterations help sustain heart function with age. However, identification of compensatory remodeling events in the aging heart remains elusive. Here we present the proteomes of rhesus monkeys and rats, from which we show that age-associated remodeling of the cardiomyocyte cytoskeleton is highly-conserved and beneficial rather than deleterious. Targeted transcriptomic analysis in Drosophila confirms conservation and implicates vinculin as a unique regulator of cardiac aging. Increased cardiac vinculin expression reinforced the cortical cytoskeleton and enhanced myofilament organization, leading to improved contractility, hemodynamic stress tolerance, and lifespan. These findings suggest that the heart has molecular mechanisms to sustain function and longevity which may be assisted by therapeutic intervention.
2016-04-15 | PXD001839 | Pride
Project description:The human heart is capable of functioning for decades despite minimal cell turnover or regeneration, suggesting that molecular alterations help sustain heart function with age. However, identification of compensatory remodeling events in the aging heart remains elusive. Here we present the proteomes of rhesus monkeys and rats, from which we show that age-associated remodeling of the cardiomyocyte cytoskeleton is highly-conserved and beneficial rather than deleterious. Targeted transcriptomic analysis in Drosophila confirms conservation and implicates vinculin as a unique regulator of cardiac aging. Increased cardiac vinculin expression reinforced the cortical cytoskeleton and enhanced myofilament organization, leading to improved contractility, hemodynamic stress tolerance, and lifespan. These findings suggest that the heart has molecular mechanisms to sustain function and longevity which may be assisted by therapeutic intervention.
2018-10-19 | PXD001842 | Pride
Project description:Aging is associated with extensive remodeling of the heart, including basement membrane (BM) components that surround cardiomyocytes. Remodeling is thought to impair cardiac mechanotransduction, but the contribution of specific BM components to age-related lateral communication between cardiomyocytes is unclear. Using a genetically tractable, rapidly aging model with sufficient cardiac genetic homology and morphology, e.g. Drosophila melanogaster, we observed differential regulation of BM collagens between laboratory strains, correlating with changes in muscle physiology leading to cardiac dysfunction. Therefore, we sought to understand the extent to which BM proteins modulate contractile function during aging. Cardiac-restricted knockdown of ECM genes Pericardin, Laminin A, and Viking in Drosophila prevented age-associated heart tube restriction and increased contractility, even under viscous load. Most notably, reduction of Laminin A expression correlated with an overall preservation of contractile velocity with age and extension of organismal lifespan. Global heterozygous knockdown confirmed these data, which provides new evidence of a direct link between BM homeostasis, contractility, and maintenance of lifespan.
2017-03-27 | PXD006120 | Pride
Project description:Mitochondrial networks provide coordinated energy distribution throughout muscle cells. However, pathways specifying mitochondrial network-type separately from contractile fiber-type remain unclear. Here, we show that natural energetic demands placed on Drosophila melanogaster muscles yield native cell-types among which contractile and mitochondrial network-types are regulated independently. Proteomic analyses of indirect flight, jump, and leg muscles together with muscles misexpressing known fiber-type specification factor salm identified transcription factors H15 and cut as potential mitochondrial network regulators. We demonstrate H15 operates downstream of salm regulating flight muscle contractile and mitochondrial network-type. Conversely, H15 regulates mitochondrial network configuration but not contractile type in jump and leg muscles. Further, we find that cut regulates salm expression in flight muscles and mitochondrial network configuration in leg muscles. These data indicate cell type-specific regulation of muscle mitochondrial network organization separately from contractile type, mitochondrial content, and mitochondrial size through an evolutionarily conserved pathway involving cut, salm, and H15.
| MSV000088173 | MassIVE
Project description:A proliferated and post-translationally modified microtubule network underlies cellular growth in cardiac hypertrophy and contributes to contractile dysfunction in heart failure. Yet how the heart achieves this modified network is poorly understood. Determining how the “tubulin code” – the permutations of tubulin isoforms and post-translational modifications - is rewritten upon cardiac stress may provide new targets to modulate cardiac remodeling. Further, while tubulin can autoregulate its own expression, it is unknown if autoregulation is operant in the heart or tuned in response to stress. Here we use heart failure patient samples and murine models of cardiac remodeling to interrogate transcriptional, autoregulatory, and post-translational mechanisms that contribute to microtubule network remodeling at different stages of heart disease. We find that autoregulation is operant across tubulin isoforms in the heart and leads to an apparent disconnect in tubulin mRNA and protein levels in heart failure. We also find that within 4 hours of a hypertrophic stimulus and prior to cardiac growth, microtubule detyrosination is rapidly induced to help stabilize the network. This occurs concomitant with rapid transcriptional and autoregulatory activation of specific tubulin isoforms and microtubule motors. Upon continued hypertrophic stimulation, there is an increase in post-translationally modified microtubule tracks and anterograde motors to support cardiac growth, while total tubulin content increases through progressive transcriptional and autoregulatory induction of tubulin isoforms. Our work provides a new model for how the tubulin code is rapidly rewritten to establish a proliferated, stable microtubule network that drives cardiac remodeling, and provides the first evidence of tunable tubulin autoregulation during pathological progression.
2022-01-28 | GSE194394 | GEO
Project description:A proliferated and post-translationally modified microtubule network underlies cellular growth in cardiac hypertrophy and contributes to contractile dysfunction in heart failure. Yet how the heart achieves this modified network is poorly understood. Determining how the “tubulin code” – the permutations of tubulin isoforms and post-translational modifications - is rewritten upon cardiac stress may provide new targets to modulate cardiac remodeling. Further, while tubulin can autoregulate its own expression, it is unknown if autoregulation is operant in the heart or tuned in response to stress. Here we use heart failure patient samples and murine models of cardiac remodeling to interrogate transcriptional, autoregulatory, and post-translational mechanisms that contribute to microtubule network remodeling at different stages of heart disease. We find that autoregulation is operant across tubulin isoforms in the heart and leads to an apparent disconnect in tubulin mRNA and protein levels in heart failure. We also find that within 4 hours of a hypertrophic stimulus and prior to cardiac growth, microtubule detyrosination is rapidly induced to help stabilize the network. This occurs concomitant with rapid transcriptional and autoregulatory activation of specific tubulin isoforms and microtubule motors. Upon continued hypertrophic stimulation, there is an increase in post-translationally modified microtubule tracks and anterograde motors to support cardiac growth, while total tubulin content increases through progressive transcriptional and autoregulatory induction of tubulin isoforms. Our work provides a new model for how the tubulin code is rapidly rewritten to establish a proliferated, stable microtubule network that drives cardiac remodeling, and provides the first evidence of tunable tubulin autoregulation during pathological progression.
2022-01-28 | GSE194393 | GEO
Project description:A proliferated and post-translationally modified microtubule network underlies cellular growth in cardiac hypertrophy and contributes to contractile dysfunction in heart failure. Yet how the heart achieves this modified network is poorly understood. Determining how the “tubulin code” – the permutations of tubulin isoforms and post-translational modifications - is rewritten upon cardiac stress may provide new targets to modulate cardiac remodeling. Further, while tubulin can autoregulate its own expression, it is unknown if autoregulation is operant in the heart or tuned in response to stress. Here we use heart failure patient samples and murine models of cardiac remodeling to interrogate transcriptional, autoregulatory, and post-translational mechanisms that contribute to microtubule network remodeling at different stages of heart disease. We find that autoregulation is operant across tubulin isoforms in the heart and leads to an apparent disconnect in tubulin mRNA and protein levels in heart failure. We also find that within 4 hours of a hypertrophic stimulus and prior to cardiac growth, microtubule detyrosination is rapidly induced to help stabilize the network. This occurs concomitant with rapid transcriptional and autoregulatory activation of specific tubulin isoforms and microtubule motors. Upon continued hypertrophic stimulation, there is an increase in post-translationally modified microtubule tracks and anterograde motors to support cardiac growth, while total tubulin content increases through progressive transcriptional and autoregulatory induction of tubulin isoforms. Our work provides a new model for how the tubulin code is rapidly rewritten to establish a proliferated, stable microtubule network that drives cardiac remodeling, and provides the first evidence of tunable tubulin autoregulation during pathological progression.
2022-01-28 | GSE194392 | GEO
Project description:A proliferated and post-translationally modified microtubule network underlies cellular growth in cardiac hypertrophy and contributes to contractile dysfunction in heart failure. Yet how the heart achieves this modified network is poorly understood. Determining how the “tubulin code” – the permutations of tubulin isoforms and post-translational modifications - is rewritten upon cardiac stress may provide new targets to modulate cardiac remodeling. Further, while tubulin can autoregulate its own expression, it is unknown if autoregulation is operant in the heart or tuned in response to stress. Here we use heart failure patient samples and murine models of cardiac remodeling to interrogate transcriptional, autoregulatory, and post-translational mechanisms that contribute to microtubule network remodeling at different stages of heart disease. We find that autoregulation is operant across tubulin isoforms in the heart and leads to an apparent disconnect in tubulin mRNA and protein levels in heart failure. We also find that within 4 hours of a hypertrophic stimulus and prior to cardiac growth, microtubule detyrosination is rapidly induced to help stabilize the network. This occurs concomitant with rapid transcriptional and autoregulatory activation of specific tubulin isoforms and microtubule motors. Upon continued hypertrophic stimulation, there is an increase in post-translationally modified microtubule tracks and anterograde motors to support cardiac growth, while total tubulin content increases through progressive transcriptional and autoregulatory induction of tubulin isoforms. Our work provides a new model for how the tubulin code is rapidly rewritten to establish a proliferated, stable microtubule network that drives cardiac remodeling, and provides the first evidence of tunable tubulin autoregulation during pathological progression.
2022-01-28 | GSE194391 | GEO
Project description:Aging of skeletal muscle tissue is characterized by loss of metabolic and contractile competence. It is thought that this phenomenon is driven via extrinsic and intrinsic factors. In order to identify age-dependent changes intrinsic to the muscle cell, microarray transcriptional profiles and measurements of glucose metabolism were performed in primary cultured human myotubes at different time points over seven weeks. Aging in culture tended to reduce myotube glucose metabolism, oxidative and storage capacities, despite elevation of glucose transport. The mitochondrial membrane potential slightly increased, whereas peroxidation of cell membrane lipids declined and membrane integrity was preserved. Transcriptional analysis revealed a fall in genes involved in glucose metabolism and oxidative phosphorylation, while stress defense genes were elevated. Expression of numerous genes coding for muscle contractile proteins and calcium-regulating proteins, was gradually decreased during aging of cultured myotubes. Transcripts of genes involved in cell growth, matrix and motility markedly rose while those involved in cell adhesion dropped. In conclusion, aging myotubes in culture exhibit a loss of glucose metabolic capacity. They are characterized by a shift from a contractile to a growth-survival, matrix-remodeling phenotype. This pattern of changes, linked to intrinsic factors, displays significant similarities with aging of muscle from primates and human subjects.
2007-07-19 | E-GEOD-1144 | biostudies-arrayexpress
Project description:Mechanical forces regulate cell behavior and tissue morphogenesis. In particular, cardiac tissues require mechanical stimuli generated by the heartbeat for differentiation and maturation, but the molecular mechanisms underlying these processes remain unclear. Here, we first show that mechanical forces acting via the mechanosensitive factor Vinculin (VCL) are essential for cardiomyocyte myofilament maturation and that cardiac contractility regulates the localization and activation of Vinculin. To further analyze the role of Vinculin in myofilament maturation, we examined its interactome in contracting cardiomyocytes and found many cytoskeletal factors including actinins. We also identified Slingshot protein phosphatase 1 (SSH1), which we show is recruited by Vinculin to regulate F-actin rearrangement and myofilament maturation through its association with the actin depolymerizing factor Cofilin (CFL). Together, our results reveal that mechanical forces generated by cardiac contractility regulate cardiomyocyte maturation through the VCL-SSH1-CFL axis, providing mechanistic insight into how mechanical forces are transmitted intracellularly to regulate myofilament maturation.
2019-09-06 | PXD014624 | Pride