Estrogen receptor alpha deficiency in cardiomyocytes reprograms the heart-derived extracellular vesicle proteome and induces obesity in female mice

Tham, Yow Keat; Bernardo, Bianca C.; Claridge, Bethany; Yildiz, Gunes S.; Woon, Lam Pin; Bond, Simon T.; Fang, Haoyun; Ooi, Jenny Y. Y.; Matsumoto, Aya; Luo, Jieting; Tai, Celeste Ming-Kay; Harmawan, Claudia A.; Kiriazis, Helen; Donner, D.; Mellett, Natalie A.; Abel, E. Dale; Khan, Sohaib A.; Souza, David P De; Doomun, Sheik Nadeem Elahee; Liu, Kevin; Xiang, Ruidong; Singh, Manika; Inouye, Michael; Meikle, Peter J.; Weeks, Kate L.; Drew, Brian G.; Greening, David W.; McMullen, Julie R.

doi:10.1038/s44161-023-00223-z

Cited by 12 publications

(3 citation statements)

References 109 publications

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“…Label free and tandem mass tag (TMT) 95 nano liquid-chromatography/mass spectrometry (nLC/MS) proteomics was performed as previously described 95,96 with some modifications.…”

Section: Methodsmentioning

confidence: 99%

Skeletal Muscle Specific PolG Dysfunction Activates the Integrated Stress Response and Promotes a Cachexia like Phenotype

Bond,

King,

Walker

et al. 2024

Preprint

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During mitochondrial damage, information is relayed between the mitochondria and nucleus to coordinate precise responses to preserve cellular health. One such pathway is the mitochondrial integrated stress response (mtISR), which is specifically activated by mitochondrial DNA (mtDNA) damage. However, the causal molecular signals responsible for this activation remain elusive. A gene often associated with mtDNA mutations/deletions isPolg1, which encodes the mitochondrial DNA Polymerase γ (PolG). Here, we describe what is to our knowledge the first conditional muscle specific model of PolG mutation, and demonstrate a rapid development of mitochondrial dysfunction and cachexia in these animals from ∼5 months of age. Detailed molecular profiling of muscles demonstrated robust activation of the mtISR, likely mediated upstream by the HRI/DELE1 stress pathway. This was accompanied by striking alterations to the mitochondrial folate cycle and its metabolites, strongly implying imbalanced folate intermediates as a previously unrecognised pathology driving the mtISR in mitochondrial disease.

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“…Label free and tandem mass tag (TMT) 95 nano liquid-chromatography/mass spectrometry (nLC/MS) proteomics was performed as previously described 95,96 with some modifications.…”

Section: Methodsmentioning

confidence: 99%

Skeletal Muscle Specific PolG Dysfunction Activates the Integrated Stress Response and Promotes a Cachexia like Phenotype

Bond,

King,

Walker

et al. 2024

Preprint

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“…Mouse LA (physiological model: IGF1R and Ntg littermates [labelled NTG2], pathological model: DCM-dnPI3K [HF+AF] and Ntg littermates [labelled NTG4]), were extracted and lysed on ice in lysis buffer (8 M urea in 50 mM HEPES pH 8.0 with Halt™ Protease/Phosphatase Inhibitor Cocktail (#78442, Thermo Fisher Scientific)) and extracted by pulse tip-probe sonication on ice and quantified by microBCA (#23235, Life Technologies). All samples quantified by microBCA (Thermo Fisher Scientific), normalised (10 µg) and subsequently reduced, alkylated and solid-phase interaction proteomic sample preparation performed as described [ 27 ]. Briefly, protein samples were mixed with Sera‐Mag Speed Beads (#45152105050250 and #65152105050250, GE LifeScience) at a 10:1 beads-to-protein ratio, with protein-bound-beads reconstituted and exposed to trypsin (V5113, Promega) and Lys-C (121-05063, FUJIFILM Wako Pure Chemical Corporation) at 1:50 and 1:100 enzyme-to-substrate ratio overnight at 37°C with shaking.…”

Section: Methodsmentioning

confidence: 99%

Distinct functional and molecular profiles between physiological and pathological atrial enlargement offer potential new therapeutic opportunities for atrial fibrillation

Chen,

Wijekoon,

Matsumoto

et al. 2024

Clinical Science

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Atrial fibrillation (AF) remains challenging to prevent and treat. A key feature of AF is atrial enlargement. However, not all atrial enlargement progresses to AF. Atrial enlargement in response to physiological stimuli such as exercise is typically benign and reversible. Understanding the differences in atrial function and molecular profile underpinning pathological and physiological atrial remodelling will be critical for identifying new strategies for AF. The discovery of molecular mechanisms responsible for pathological and physiological ventricular hypertrophy has uncovered new drug targets for heart failure. Studies in the atria have been limited in comparison. Here, we characterised mouse atria from 1) a pathological model (cardiomyocyte-specific transgenic (Tg) that develops dilated cardiomyopathy [DCM] and AF due to reduced protective signalling [PI3K]; DCM-dnPI3K), and 2) a physiological model (cardiomyocyte-specific Tg with an enlarged heart due to increased insulin-like growth factor 1 receptor; IGF1R). Both models presented with an increase in atrial mass, but displayed distinct functional, cellular, histological and molecular phenotypes. Atrial enlargement in the DCM-dnPI3K Tg, but not IGF1R Tg, was associated with atrial dysfunction, fibrosis and a heart failure gene expression pattern. Atrial proteomics identified protein networks related to cardiac contractility, sarcomere assembly, metabolism, mitochondria, and extracellular matrix which were differentially regulated in the models; many co-identified in atrial proteomics data sets from human AF. In summary, physiological and pathological atrial enlargement are associated with distinct features, and the proteomic dataset provides a resource to study potential new regulators of atrial biology and function, drug targets and biomarkers for AF.

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“…Within the cardiovascular system homeostasis circuitry, EV-mediated signaling reciprocity between different cell types (cardiomyocytes, endothelial cells, fibroblasts, smooth muscle cells, and inflammatory cells) occupies a unique niche: from regulating cardiomyocyte proliferation during heart development, 80 intercellular and intracellular cardiomyocyte:cardiac fibroblast signaling, 81 orchestrating glycolytic flux for normal vascular physiology 82 and muscle/myocytes through multiomic regulation, 83 to coordinating protective responses (such as angiogenesis 84 and fibrosis 85 ) during stress. [86][87][88] This knowledge has provided important ques on developing innovative EV-centric strategies for CVDs (Table 1).…”

Section: Ev Therapeutics For Cardiovascular Diseasesmentioning

confidence: 99%

The Discovery of Extracellular Vesicles and Their Emergence as a Next-Generation Therapy

Rai,

Claridge,

Lozano

et al. 2024

Circulation Research

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From their humble discovery as cellular debris to cementing their natural capacity to transfer functional molecules between cells, the long-winded journey of extracellular vesicles (EVs) now stands at the precipice as a next-generation cell-free therapeutic tool to revolutionize modern-day medicine. This perspective provides a snapshot of the discovery of EVs to their emergence as a vibrant field of biology and the renaissance they usher in the field of biomedical sciences as therapeutic agents for cardiovascular pathologies. Rapid development of bioengineered EVs is providing innovative opportunities to overcome biological challenges of natural EVs such as potency, cargo loading and enhanced secretion, targeting and circulation half-life, localized and sustained delivery strategies, approaches to enhance systemic circulation, uptake and lysosomal escape, and logistical hurdles encompassing scalability, cost, and time. A multidisciplinary collaboration beyond the field of biology now extends to chemistry, physics, biomaterials, and nanotechnology, allowing rapid development of designer therapeutic EVs that are now entering late-stage human clinical trials.

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Estrogen receptor alpha deficiency in cardiomyocytes reprograms the heart-derived extracellular vesicle proteome and induces obesity in female mice

Cited by 12 publications

References 109 publications

Skeletal Muscle Specific PolG Dysfunction Activates the Integrated Stress Response and Promotes a Cachexia like Phenotype

Skeletal Muscle Specific PolG Dysfunction Activates the Integrated Stress Response and Promotes a Cachexia like Phenotype

Distinct functional and molecular profiles between physiological and pathological atrial enlargement offer potential new therapeutic opportunities for atrial fibrillation

The Discovery of Extracellular Vesicles and Their Emergence as a Next-Generation Therapy

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