Muscle injury, impaired muscle function and insulin resistance in Chromogranin A-knockout mice

Tang, Kechun; Pasqua, Teresa; Biswas, Angshuman; Mahata, Sumana; Tang, Jennifer; Tang, Alisa; Bandyopadhyay, Gautam; Sinha‐Hikim, Amiya P.; Chi, Nai‐Wen; Webster, Nicholas J. G.; Corti, Angelo; Mahata, Sushil K.

doi:10.1530/joe-16-0370

Cited by 10 publications

(5 citation statements)

References 86 publications

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“…The number of mitochondria per field of µm 2 and the mitochondrial cross-sectional area were quantified. For the determination of cristae density, the outer membrane and the cristae membrane were manually traced, and the sum of the cristae area were divided by the outer area of the mitochondria, as described previously 38 . All measurements were performed by ImageJ 1.52 software.…”

Section: Methodsmentioning

confidence: 99%

Cardiac-specific loss of mitoNEET expression is linked with age-related heart failure

et al. 2021

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Heart failure (HF) occurs frequently among older individuals, and dysfunction of cardiac mitochondria is often observed. We here show the cardiac-specific downregulation of a certain mitochondrial component during the chronological aging of mice, which is detrimental to the heart. MitoNEET is a mitochondrial outer membrane protein, encoded by CDGSH iron sulfur domain 1 (CISD1). Expression of mitoNEET was specifically downregulated in the heart and kidney of chronologically aged mice. Mice with a constitutive cardiac-specific deletion of CISD1 on the C57BL/6J background showed cardiac dysfunction only after 12 months of age and developed HF after 16 months; whereas irregular morphology and higher levels of reactive oxygen species in their cardiac mitochondria were observed at earlier time points. Our results suggest a possible mechanism by which cardiac mitochondria may gradually lose their integrity during natural aging, and shed light on an uncharted molecular basis closely related to age-associated HF.

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Section: Methodsmentioning

confidence: 99%

Cardiac-specific loss of mitoNEET expression is linked with age-related heart failure

et al. 2021

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“…Radioactivity in the lower chloroform layer was determined by measuring fatty acids in the aqueous layer by determining acid soluble metabolites (ASM, representing fatty acid oxidation) as described previously by us (86).…”

Section: Real Time Pcrmentioning

confidence: 99%

The immunosuppression of macrophages underlies the cardioprotective effects of catestatin (CST)

Ying

Tang

Avolio

et al. 2020

Preprint

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38Objective: Hypertension (HTN) is a global pandemic, affecting more than one billion people. 39Although catestatin (CST), a chromogranin A (CgA)-derived peptide, decreases blood pressure 40 (BP) in rodent models of HTN, the mechanisms underlying its hypotensive action is yet to be 41 established. Here we generated CST knockout (CST-KO) mice to pinpoint the mechanism of the 42 hypotensive action of CST. 44Methods and Results: CST-KO mice were hypertensive; their serum cytokines were elevated, 45 anti-inflammatory genes were downregulated, and their hearts showed marked infiltration with 46 macrophages. CST replenishment reversed all these phenotypes -it normalized BP, reduced 47 serum cytokines, upregulated anti-inflammatory genes, and reduced the cardiac infiltrates by 48 ~30%, as determined by FACS. Pre-conditioning-induced cardioprotection was also abolished in 49 CST-KO mice. We hypothesize that CST's anti-hypertensive and cardioprotective effects may be 50 caused by suppressed trafficking of macrophages to the heart and reduced inflammation. Such 51 cause-and-effect relationship is supported by the fact that CST-KO mice became normotensive 52 when they were depleted of macrophages using chlodronate, or when they received bone marrow 53 transplant from wild-type littermates. Mechanistically, cardiac tissue transcriptomes revealed 54 multiple altered gene expression programs in CST-KO mice that are commonly encountered in 55 human cardiomyopathies. Among others, a prominent reduction of Glo1 gene was seen in CST-56 KO mice; supplementation with CST increased it expression by >7-fold. Because Glo1 in 57 macrophages metabolizes methylglyoxal, an inflammatory agent whose accumulation promotes 58 vascular damage in HTN and T2DM, this could be one of the means by which CST attenuates 59 inflammation and improves cardiovascular health. Repletion of CST also improved glucose 60 metabolism and increased the surface area of mitochondrial cristae and decreased the secretion 61 of catecholamines; the latter explains the anti-hypertensive actions of CST. 63Conclusions: We conclude that the anti-hypertensive effects of CST is mediated at least in part 64 via CST's anti-inflammatory actions; in the absence of CST, macrophages are more reactive, they 65 infiltrate the heart and alter the ultrastructure, physiologic and molecular makeup of the 66 myocardium. These studies implicate CST as a key mediator of the observed crosstalk between 67 systemic and cardiac inflammation in HTN.68 69 70 71 3 Abbreviations 72 2DG: 2-deoxy-glucose 73 Actc1: cardiac muscle actin alpha 74 Atp5j: mitochondrial ATP synthase subunit F6 75 BRS: baroreflex sensitivity 76 Cd36: cluster of differentiation 36 77 Cers2: ceramide synthase 2 78 CgA: chromogranin A 79 CST: catestatin 80 CST-KO: CST knockout Introduction 122 123 Hypertension (HTN) is an important risk factor for cardiovascular disease (CVD) and mortality 1 .124 The burden of HTN and the estimated HTN-associated deaths have increased substantially over 125 the past 25 years 2 .126 The role o...

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“…CHGA knockout (CgA-KO) mice are obese on normal chow diet [113], have significantly higher glucosestimulated insulin secretion after glucose administration [114], have hypertension with higher catecholamine levels [113], and have insulin resistance in muscle cells [115]. Lower triglyceride levels have been found in CgA--KO mice, despite similar amounts of fatty tissue [116].…”

Section: Chromogranin a In Type 2 Diabetes Mellitusmentioning

confidence: 99%

Chromogranina A i jej rola w patogenezie cukrzycy

Herold

Doleschall²,

Kövesdi

et al. 2018

Endokrynologia Polska

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Chromogranin A is a member of the granin glycoprotein family that is expressed by the endocrine and neuroendocrine cells of different organs. Intracellularly, Chromogranin A contributes to the regulation of secretion, and gives several cleavage products after secretion. Some of its cleavage products modify the hormone functions in autocrine and paracrine ways, while the functions of others have not been fully understood yet. Serum Chromogranin A level is most prominently used in neuroendocrine tumor diagnostics. In addition, recent studies have suggested that Chromogranin A and some of its cleavage products, pancreastatin and WE-14, also play important roles in the pathogenesis of the various forms of diabetes mellitus, but their exact mechanisms still need to be clarified. Higher Chromogranin A, pancreastatin and WE-14 levels have been reported in type 1, type 2 and gestational diabetic patients compared to healthy controls. A notable connection has been inferred through the observation that type 1 diabetes mellitus is not at all or rarely developed in Chromogranin A gene-knockout, non-obese diabetic model mice compared to non-knockout, non-obese diabetic mice. Pancreastatin inhibits insulin release in various cell and animal models, and WE-14 serves as an autoantigen for both CD4+ and CD8+ beta cell-destructive diabetogenic T-cell clones in type 1 diabetes. Chromogranin A contributes to the pathogenesis of diabetes mellitus according to the available literature. The current findings facilitate further investigation to unravel the deeper relationships between this glycoprotein and diabetes.

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Muscle injury, impaired muscle function and insulin resistance in Chromogranin A-knockout mice

Cited by 10 publications

References 86 publications

Cardiac-specific loss of mitoNEET expression is linked with age-related heart failure

Cardiac-specific loss of mitoNEET expression is linked with age-related heart failure

The immunosuppression of macrophages underlies the cardioprotective effects of catestatin (CST)

Chromogranina A i jej rola w patogenezie cukrzycy

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