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Estrogen receptor α deficiency in cardiac myocytes reprograms heart-derived extracellular vesicle proteome and induces obesity in female mice (Part 1)

ABSTRACT: Dysregulation of ERα has been linked with increased metabolic and cardiovascular disease risk. Uncovering the impact of ERα deficiency in specific tissues has implications for understanding the role of ERα in normal physiology and disease, the increased disease risk in postmenopausal women, and the design of tissue-specific ERα-based therapies for a range of pathologies including cardiac disease and cancer. Cardiac myocyte-specific ER knockout mice (ERαHKO) were generated to assess the role of ERα in the heart. Female ERαHKO mice displayed a modest cardiac phenotype, but unexpectedly, the most striking phenotype was obesity in female ERαHKO but not male ERαHKO mice. In female ERαHKO mice we identified cardiac dysfunction, mild glucose and insulin intolerance, and reduced ERα gene expression in skeletal muscle and white adipose tissue (WAT). Gene expression, protein, lipidomic and metabolomic analyses showed evidence of contractile and/or metabolic dysregulation in heart, skeletal muscle and WAT. We also show that extracellular vesicles (EVs) collected from the perfusate of isolated hearts from female ERαHKO mice have a distinct proteome, and these EVs have the capacity to reprogram the proteome of a skeletal muscle cell including proteins linked with ERα, fatty acid regulation, lipid metabolism and mitochondrial function. This study uncovers a cardiac-initiated and sex-specific cardiometabolic phenotype that is regulated by ERα.

ORGANISM(S): Mouse Mus Musculus

TISSUE(S): Liver, Muscle, Epididymal Fat, Ventricles, Blood

DISEASE(S): Obesity

SUBMITTER: Yow Keat Tham

PROVIDER: ST002229 | MetabolomicsWorkbench | Wed May 18 00:00:00 BST 2022

REPOSITORIES: MetabolomicsWorkbench

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Estrogen receptor a deficiency in cardiac myocytes reprograms heart-derived extracellular vesicle proteome and induces obesity in female mice (Part 2)

Project description:Dysregulation of ERα has been linked with increased metabolic and cardiovascular disease risk. Uncovering the impact of ERα deficiency in specific tissues has implications for understanding the role of ERα in normal physiology and disease, the increased disease risk in postmenopausal women, and the design of tissue-specific ERα-based therapies for a range of pathologies including cardiac disease and cancer. Cardiac myocyte-specific ER knockout mice (ERαHKO) were generated to assess the role of ERα in the heart. Female ERαHKO mice displayed a modest cardiac phenotype, but unexpectedly, the most striking phenotype was obesity in female ERαHKO but not male ERHKO mice. In female ERαHKO mice we identified cardiac dysfunction, mild glucose and insulin intolerance, and reduced ERα gene expression in skeletal muscle and white adipose tissue (WAT). Gene expression, protein, lipidomic and metabolomic analyses showed evidence of contractile and/or metabolic dysregulation in heart, skeletal muscle and WAT. We also show that extracellular vesicles (EVs) collected from the perfusate of isolated hearts from female ERαHKO mice have a distinct proteome, and these EVs have the capacity to reprogram the proteome of a skeletal muscle cell including proteins linked with ERα, fatty acid regulation, lipid metabolism and mitochondrial function. This study uncovers a cardiac-initiated and sex-specific cardiometabolic phenotype that is regulated by ERα.

2022-07-17 | ST002228 | MetabolomicsWorkbench

RNA-seq of ventricle and fat tissues of male and female cardiac myocyte-specific estrogen receptor KO mice

Project description:Cardiac myocyte-specific ERalpha KO mice were generated to assess the role of ERα in the heart. Female ERαHKO mice displayed a modest cardiac phenotype, but unexpectedly, an the most striking obesity phenotype developed was obesity in female ERαHKO but not male ERαHKO mice. In female ERαHKO mice we identified cardiac dysfunction, mild glucose and insulin intolerance, and reduced ERα gene expression in skeletal muscle and white adipose tissue (WAT). RNA-seq analysis was conducted on the ventricles and WAT of male and female ERαHKO mice to further elucidate the transcriptomic alterations associated with the shift in metabolic profiles in the tissues of interest.

2023-01-24 | E-MTAB-12564 | biostudies-arrayexpress

Heart-derived extracellular vesicles reprogram smooth muscle cells

Project description:Dysregulation of ER has been linked with increased metabolic and cardiovascular disease risk. Uncovering the impact of ERα deficiency in specific tissues has implications for understanding the role of ERα in normal physiology and disease, the increased disease risk in postmenopausal women, and the design of tissue-specific ERα-based therapies for a range of pathologies including cardiac disease and cancer. Cardiac myocyte-specific ER knockout mice (ERHKO) were generated to assess the role of ERα in the heart. Female ERHKO mice displayed a mild cardiac phenotype, but unexpectedly, the most striking phenotype was obesity in female ERHKO but not male ERHKO mice. We identified mild cardiac dysfunction, metabolic and lipid dysregulation in hearts of female ERHKO mice. We also show that extracellular vesicles (EVs) collected from the perfusate from Langendorff-isolated hearts from female ERHKO mice have a distinct proteome compared to male ERHKO; enriched for functions associated with muscle, metabolic and fatty acid dysregulation.

2023-01-15 | PXD033078 | Pride

Heart tissue extracellular vesicles reprogram smooth muscle cell proteome

Project description:Dysregulation of ERalpha has been linked with increased metabolic and cardiovascular disease risk. Uncovering the impact of ERα deficiency in specific tissues has implications for understanding the role of ERα in normal physiology and disease, the increased disease risk in postmenopausal women, and the design of tissue-specific ERα-based therapies for a range of pathologies including cardiac disease and cancer. Cardiac myocyte-specific ER knockout mice (ERalphaHKO) were generated to assess the role of ERα in the heart. Female ERHKO mice displayed a mild cardiac phenotype, but unexpectedly, the most striking phenotype was obesity in female ERHKO but not male ERHKO mice. We identified mild cardiac dysfunction, metabolic and lipid dysregulation in hearts of female ERHKO mice. We also show that extracellular vesicles (EVs) collected from the perfusate from Langendorff-isolated hearts from female ERHKO mice have a distinct proteome compared to male ERHKO; enriched for functions associated with muscle, metabolic and fatty acid dysregulation.

2023-01-15 | PXD038482 | Pride

Extracellular vesicle proteome from cardiac muscle critical for protection against obesity in female mice

Project description:Dysregulation of ER has been linked with increased metabolic and cardiovascular disease risk. Uncovering the impact of ERα deficiency in specific tissues has implications for understanding the role ERα in normal physiology and disease, the increased disease risk in postmenopausal women, and the design of tissue-specific ERα-based therapies for a range of pathologies including cardiac disease and cancer. Cardiac myocyte-specific ER knockout mice (ERHKO) were generated to assess the role of ERα in the heart. Female ERHKO mice displayed a mild cardiac phenotype, but unexpectedly, the most striking phenotype was obesity in female ERHKO but not male ERHKO mice. We identified contractile dysfunction, metabolic and lipid dysregulation in hearts of female ERHKO mice. We also show that extracellular vesicles (EVs) collected from the perfusate from Langendorff-isolated hearts from female ERHKO mice contained distinct proteins with functions related to muscle, metabolic and fatty acid dysregulation.

2023-01-15 | PXD027811 | Pride

Transcription profiling of six tissues from ATGL knock-out versus wild type mice

Project description:Gene expression profiling in 6 tissues (white adipose tissue (WAT), brown adipose tissue (BAT), cardiac muscle (CM), liver (LIV), kidney (KID), skeletal muscle (SM)) from ATGL(-/-) mice versus wildtype (ATGL+/+) mice.

2008-02-03 | E-MARS-8 | biostudies-arrayexpress

Skeletal muscle derived Musclin protects the heart during pathological overload

Project description:Cachexia is associated with poor prognosis in patients with chronic heart failure. The underlying mechanisms of cachexia triggered heart failure progression, however, are not well understood. Here, we investigated whether the dysregulation of myokine expression from wasting skeletal muscle and impaired inter-organ crosstalk during advanced heart failure might contribute to progression of the disease. RNA sequencing analysis from wasting skeletal muscles of mice with cardiac cachexia during long-term pressure overload revealed a strongly reduced expression of Ostn. Ostn encodes for the skeletal muscle derived myokine Musclin, which had been previously implicated in the enhancement of natriuretic peptide (NP) signaling. Using newly developed skeletal muscle specific, inducible Ostn knock-out mice, we demonstrated that reduced skeletal muscle Musclin levels exaggerated cardiac dysfunction and myocardial fibrosis compared to littermate control mice after TAC. Restoration of Musclin deficiency during cardiac cachexia via AAV6-mediated skeletal muscle specific Musclin overexpression, in turn, attenuated left ventricular dysfunction and myocardial fibrosis. Mechanistically, we found that Musclin enhanced CNP/NPR2/cGMP signaling in cardiomyocytes, which led to improved contractility by inhibition of the cAMP degrading phosphodiesterase (PDE)3 and augmented cAMP/protein kinase A signaling. In addition, Musclin directly acted on cardiac fibroblasts to inhibit their activation. Together, our study indicates the therapeutic potential of targeting interorgan cross-talk during heart failure, for example by counteracting the impaired secretion of the Musclin from wasting skeletal muscle.

2021-11-02 | GSE129205 | GEO

Oxidative posttranslational modifications of cysteine are associated to high intrinsic aerobic capacity in the skeletal and cardiac muscle

Project description:Oxidative posttranslational modifications (Ox-PTMs) regulate cellular homeostasis in several tissues, including skeletal and cardiac muscles. The putative relationship between Ox-PTMs and intrinsic components of oxidative energy metabolism has not been previously described. We determined the metabolic phenotype and the Ox-PTM profile in the skeletal and cardiac muscles of rats selected for low (LCR) or high (HCR) intrinsic aerobic capacity. The HCR rats have a pronounced increase in mitochondrial content and antioxidant capacity when compared to LCR rats in the skeletal muscle, but only modest changes in the cardiac muscle. Redox proteomics analysis reveals that HCR and LCR rats have different Ox-PTM of cysteine (Cys) residue profile in the skeletal and cardiac muscles. HCR rats have higher number of oxidized Cys residues in the skeletal muscle and conversely display higher number of reduced Cys residues in the cardiac muscle than LCR rats. Most of the proteins with differentially oxidized Cys residues in the skeletal muscle are important regulators of the oxidative metabolism. The most significantly oxidized protein in the skeletal muscle of HCR rats is malate dehydrogenase (MDH1). Interestingly, HCR rats show higher MDH1 activity in the skeletal muscle, but not in the cardiac muscle. Thus, this study uncovers an association between Ox-PTMs and intrinsic aerobic capacity, providing new insights into the role of Ox-PTMs as essential signaling to maintain metabolic homeostasis in different muscle types.

2019-11-12 | PXD009109 | Pride

MicroRNA profiling of mouse white adipose tissue, brown adipose tissue and skeletal muscle

Project description:Compare miRNA expression profiles in epididymal white adipose tissue (WAT), interscapular brown adipose tissue (BAT) and skeletal muscle from wild-type C57BL/6J mice

2010-12-01 | E-MEXP-2553 | biostudies-arrayexpress

Anti-inflammatory nutrition with high protein attenuates cardiac and skeletal muscle alterations in a pulmonary arterial hypertension model

Project description:Pulmonary arterial hypertension (PAH) is characterized by remodelling of the pulmonary arteries and right ventricle (RV), which leads to functional decline of cardiac and skeletal muscle. This study investigated the effects of a multi-targeted nutritional intervention with extra protein, leucine, fish oil and oligosaccharides on cardiac and skeletal muscle in PAH. PAH was induced in female C57BL/6 mice by weekly injections of monocrotaline (MCT) for 8 weeks. Control diet (sham and MCT group) and isocaloric nutritional intervention (MCT + NI) were administered. Compared to sham, MCT mice increased heart weight by 7%, RV thickness by 13% and fibrosis by 60% (all p < 0.05) and these were attenuated in MCT + NI mice. Microarray and qRT-PCR analysis of RV confirmed effects on fibrotic pathways. Skeletal muscle fiber atrophy was induced (P < 0.05) by 22% in MCT compared to sham mice, but prevented in MCT + NI group. Our findings show that a multi-targeted nutritional intervention attenuated detrimental alterations to both cardiac and skeletal muscle in a mouse model of PAH, which provides directions for future therapeutic strategies targeting functional decline of both tissues.

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