Dietary genistein enhances phosphorylation of regulatory myosin light chain in the myocardium of ovariectomized mice

Schwab, Karima; Stein, Robert; Scheler, Christian; Theuring, Franz

doi:10.1002/elps.201100607

Cited by 5 publications

(4 citation statements)

References 44 publications

(50 reference statements)

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“…These data extend previous reports of E 2 affecting skeletal muscle force generation (16,38,39,43,66) and provide insight into a specific molecular modification of myosin as an underlying mechanism. E 2 , as well as the estrogenic compound genistein, has previously been shown to enhance pRLC in other cell types including mouse cardiac muscle (24,54). Consistent with those results, the current study provides evidence that E 2 increased pRLC in a skeletal muscle cell line ( Fig.…”

Section: Discussionsupporting

confidence: 91%

“…Similarly, PI3K and Akt are involved in modulating pRLC mediated by E 2 , which is consistent with E 2 -mediated PI3K signaling in smooth muscle contraction (19). ROCK has been shown to mediate pRLC by decreasing myosin light chain phosphatase activity and/or directly phosphorylating RLC (1,54,57,62). Our findings demonstrate that inhibition of ROCK led to decreased E 2 -induced pRLC by 26%.…”

Section: Discussionsupporting

confidence: 86%

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Estradiol modulates myosin regulatory light chain phosphorylation and contractility in skeletal muscle of female mice

Lai

Collins

Colson

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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-Impairment of skeletal muscle function has been associated with changes in ovarian hormones, especially estradiol. To elucidate mechanisms of estradiol on skeletal muscle strength, the hormone's effects on phosphorylation of the myosin regulatory light chain (pRLC) and muscle contractility were investigated, hypothesizing an estradiol-specific beneficial impact. In a skeletal muscle cell line, C 2C12, pRLC was increased by 17␤-estradiol (E 2) in a concentration-dependent manner. In skeletal muscles of C57BL/6 mice that were E 2 deficient via ovariectomy (OVX), pRLC was lower than that from ovary-intact, sham-operated mice (Sham). The reduced pRLC in OVX muscle was reversed by in vivo E 2 treatment. Posttetanic potentiation (PTP) of muscle from OVX mice was low compared with that from Sham mice, and this decrement was reversed by acute E 2 treatment, demonstrating physiological consequence. Western blot of those muscles revealed that low PTP corresponded with low pRLC and higher PTP with greater pRLC. We aimed to elucidate signaling pathways affecting E 2-mediated pRLC using a kinase inhibitor library and C 2C12 cells as well as a specific myosin light chain kinase inhibitor in muscles. PI3K/Akt, MAPK, and CamKII were identified as candidate kinases sensitive to E 2 in terms of phosphorylating RLC. Applying siRNA strategy in C 2C12 cells, pRLC triggered by E 2 was found to be mediated by estrogen receptor-␤ and the G protein-coupled estrogen receptor. Together, these results provide evidence that E 2 modulates myosin pRLC in skeletal muscle and is one mechanism by which this hormone can affect muscle contractility in females. estrogen; estrogen receptor; kinase; post tetanic potentiation; RLC OVARIAN HORMONE DEFICIENCY is related to muscle dysfunction and loss of strength. For example, declines in strength are accelerated around the time of menopause (35,41,51), and skeletal muscles of postmenopausal women on estrogen-based hormone therapy are stronger than those not on hormone therapy (10,17,49). In mouse models, contractile characteristics are impaired in muscles of ovariectomized compared with sham-operated mice (16,38,39,53,65). It was suggested (41) and subsequently demonstrated that ovarian hormones influence muscle strength by directly affecting the function of contractile proteins (43,66), particularly the structure and function of myosin (38,39). Among the ovarian hormones, 17␤-estradiol (E 2 ) appears to be the key hormone, because it reverses muscle weakness and contractile protein dysfunction caused by ovariectomy. Specifically, reduced muscle and contractile protein functions were restored when E 2 was administered to ovariectomized mice (16,38,53). In a chemical model of premature aging, of which the ovaries of young adult mice were locally and specifically induced to be senescent, E 2 treatment improved some muscle contractile functions (18). Although these studies have demonstrated that E 2 impacts muscle and myosin functions, the molecular mechanisms by which this hormone affects the structure a...

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 86%

Estradiol modulates myosin regulatory light chain phosphorylation and contractility in skeletal muscle of female mice

Lai

Collins

Colson

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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“…The possible mechanism is summarized in Figure 9. Genistein, a phytoestrogen found in soy, has been demonstrated to afford beneficial effects on the cardiovascular system partially by reducing blood pressure and improving lipid profile (Schwab et al, 2012). A recent study has shown that genistein can reverse pulmonary hypertension and prevent right ventricular failure (Matori et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Genistein alleviates pressure overload‐induced cardiac dysfunction and interstitial fibrosis in mice

Qin

Zhang

et al. 2015

British J Pharmacology

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Background and Purpose Pressure overload‐induced cardiac interstitial fibrosis is viewed as a major cause of heart failure in patients with hypertension or aorta atherosclerosis. The purpose of this study was to investigate the effects and the underlying mechanisms of genistein, a natural phytoestrogen found in soy bean extract, on pressure overload‐induced cardiac fibrosis. Experimental Approach Genisten was administered to mice with pressure overload induced by transverse aortic constriction. Eight weeks later, its effects on cardiac dysfunction, hypertrophy and fibrosis were determined. Its effects on proliferation, collagen production and myofibroblast transformation of cardiac fibroblasts (CFs) and the signalling pathways were also assessed in vitro. Key Results Pressure overload‐induced cardiac dysfunction, hypertrophy and fibrosis were markedly attenuated by genistein. In cultured CFs, genistein inhibited TGFβ1‐induced proliferation, collagen production and myofibroblast transformation. Genistein suppressed TGFβ‐activated kinase 1 (TAK1) expression and produced anti‐fibrotic effects by blocking the TAK1/MKK4/JNK pathway. Further analysis indicated that it up‐regulated oestrogen‐dependent expression of metastasis‐associated gene 3 (MTA3), which was found to be a negative regulator of TAK1. Silencing MTA3 by siRNA, or inhibiting the activity of the MTA3‐NuRD complex with trichostatin A, abolished genistein's anti‐fibrotic effects. Conclusions and Implications Genistein improved cardiac function and inhibited cardiac fibrosis in response to pressure overload. The underlying mechanism may involve regulation of the MTA3/TAK1/MKK4/JNK signalling pathway. Genistein may have potential as a novel agent for prevention and therapy of cardiac disorders associated with fibrosis. Linked Articles This article is part of a themed section on Chinese Innovation in Cardiovascular Drug Discovery. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-23

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“…Many studies have indicated that female sex hormone deprivation induced by OVX shifted the expression of cardiac Myh chain isoforms from predominantly α-isoforms toward more β-isoforms [41, 42]. However, the expression of regulatory Myl chains in the myocardium of OVX mice or humans increased [43, 44]. Estrogen supplementation consistently abolished all these changes [45, 46].…”

Section: Discussionmentioning

confidence: 99%

The protective effect of Er-Xian decoction against myocardial injury in menopausal rat model

Zhang

Xiang

Zhao

et al. 2018

BMC Complement Altern Med

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BackgroundEr-Xian decoction (EXD), a formula of Chinese medicine, is often used to treat menopausal syndrome in China. The aim of the present study was to explore the potential cardioprotective mechanism of EXD against myocardial injury in an ovariectomy-induced menopausal rat model.MethodsWe divided the female Wistar rats into ovariectomy group and sham operation group (SHAM group). The ovariectomized (OVX) rats received treatment of vehicle (OVX group), EXD (EXD group) or 17β-estradiol (E2 group). After 12-week of treatment, the level of estradiol in serum was detected using an electrochemiluminescence immunoassay, and electrophysiologic changes in myocardial action potentials (AP) were evaluated using intracellular microelectrode technique. Changes in the histopathology of the left ventricle and the ultrastructure of the cardiomyocytes were observed by hematoxylin and eosin (HE) staining and transmission electronmicroscopy to assess myocardial injury. Microarrays were applied for the evaluation of gene expression profiles in ventricular muscle of the OVX and EXD rats. Further pathway analyses of the differential expression genes were carried out using the Kyoto Encyclopedia of Genes and Genomes (KEGG). And real-time quantitative RT-PCR (qRT-PCR) was used for verification of the key findings.ResultsThe results from electrophysiological and histomorphological observations demonstrated that EXD had a substantial myocardial protective effect. The EXD-treated rats, in comparison with the OVX rats, demonstrated up-regulated expression of 28 genes yet down-regulated expression of 157 genes in the ventricular muscle. The qRT-PCR assay validated all selected differential expression genes. The KEGG pathway analysis showed that the down-regulated genes were relevant to cardiomyopathy and myocardial contractility. EXD could decrease the mRNA expressions of cardiac myosin (Myh7, Myl2) and integrin (Itgb5) in the ventricular myocardium.ConclusionEXD had a protective effect against myocardial injury in OVX rats, and this cardioprotective effect may be associated with modulation of the expression of cardiac myosin or integrin at the mRNA level.Electronic supplementary materialThe online version of this article (10.1186/s12906-018-2311-9) contains supplementary material, which is available to authorized users.

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Dietary genistein enhances phosphorylation of regulatory myosin light chain in the myocardium of ovariectomized mice

Cited by 5 publications

References 44 publications

Estradiol modulates myosin regulatory light chain phosphorylation and contractility in skeletal muscle of female mice

Estradiol modulates myosin regulatory light chain phosphorylation and contractility in skeletal muscle of female mice

Genistein alleviates pressure overload‐induced cardiac dysfunction and interstitial fibrosis in mice

The protective effect of Er-Xian decoction against myocardial injury in menopausal rat model

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