Transcriptome Characterization of Estrogen-Treated Human Myocardium Identifies Myosin Regulatory Light Chain Interacting Protein as a Sex-Specific Element Influencing Contractile Function

Kararigas, Georgios; Bito, Virginie; Tinel, Hanna; Becher, Eva; Baczkó, István; Knosalla, Christoph; Albrecht-Küpper, Barbara; Sipido, Karin R.; Regitz‐Zagrosek, Vera

doi:10.1016/j.jacc.2011.09.054

Cited by 95 publications

(83 citation statements)

References 26 publications

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“…Such an acute response suggests that a nongenomic mechanism of kinase activation by E 2 may be involved. However, in some circumstances, signaling pathways for genomic and nongenomic actions of E 2 on target genes can interact (4), and E 2 has been shown to influence the expression of several members of the contractile apparatus in the heart, including myosin heavy chain, via direct gene regulation (25,26). Therefore, genomic mechanisms should not at this point be excluded, and additional studies are necessary to distinguish genomic vs. nongenomic ER mechanisms of kinase activation in skeletal muscle fibers in relation to phosphorylation of the RLC.…”

Section: Discussionmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

“…In mouse cardiomyocytes, E 2 plays a role in regulating pRLC, which correlates with contractility of those cells (24,25). Here, we hypothesized that E 2 improves skeletal muscle and myosin functions by increasing pRLC.…”

mentioning

confidence: 99%

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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“…A recent study assessed whether ex vivo treatment with E2 differentially affects male and female myocardium. 50 Indeed, E2 led to an upregulation of a different gene set in myocardial samples from men and women ( Figure 6A). 50 One of the genes that was upregulated in males only was the myosin regulatory light chain interacting protein (Mylip) gene ( Figure 6B).…”

Section: Sex-specific Gene Regulation By Estrogensmentioning

confidence: 97%

“…50 Indeed, E2 led to an upregulation of a different gene set in myocardial samples from men and women ( Figure 6A). 50 One of the genes that was upregulated in males only was the myosin regulatory light chain interacting protein (Mylip) gene ( Figure 6B). 50 Mylip binds the myosin regulatory light chain mediating its ubiquination and subsequent proteasomal degradation.…”

Section: Sex-specific Gene Regulation By Estrogensmentioning

confidence: 97%

“…50 One of the genes that was upregulated in males only was the myosin regulatory light chain interacting protein (Mylip) gene ( Figure 6B). 50 Mylip binds the myosin regulatory light chain mediating its ubiquination and subsequent proteasomal degradation. 51 Decreased myosin regulatory light chain expression is associated with decreased contractility in transgenic mice.…”

Section: Sex-specific Gene Regulation By Estrogensmentioning

confidence: 99%

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Sex and Sex Hormone–Dependent Cardiovascular Stress Responses

et al. 2013

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Mechanisms of Sex Disparities in Cardiovascular Function and Remodeling

Chaudhari

Cushen

Osikoya

et al. 2018

Comprehensive Physiology

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Epidemiological studies demonstrate disparities between men and women in cardiovascular disease prevalence, clinical symptoms, treatments, and outcomes. Enrollment of women in clinical trials is lower than men, and experimental studies investigating molecular mechanisms and efficacy of certain therapeutics in cardiovascular disease have been primarily conducted in male animals. These practices bias data interpretation and limit the implication of research findings in female clinical populations. This review will focus on the biological origins of sex differences in cardiovascular physiology, health, and disease, with an emphasis on the sex hormones, estrogen and testosterone. First, we will briefly discuss epidemiological evidence of sex disparities in cardiovascular disease prevalence and clinical manifestation. Second, we will describe studies suggesting sexual dimorphism in normal cardiovascular function from fetal life to older age. Third, we will summarize and critically discuss the current literature regarding the molecular mechanisms underlying the effects of estrogens and androgens on cardiac and vascular physiology and the contribution of these hormones to sex differences in cardiovascular disease. Fourth, we will present cardiovascular disease risk factors that are positively associated with the female sex, and thus, contributing to increased cardiovascular risk in women. We conclude that inclusion of both men and women in the investigation of the role of estrogens and androgens in cardiovascular physiology will advance our understanding of the mechanisms underlying sex differences in cardiovascular disease. In addition, investigating the role of sex‐specific factors in the development of cardiovascular disease will reduce sex and gender disparities in the treatment and diagnosis of cardiovascular disease. © 2019 American Physiological Society. Compr Physiol 9:375‐411, 2019.

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Transcriptome Characterization of Estrogen-Treated Human Myocardium Identifies Myosin Regulatory Light Chain Interacting Protein as a Sex-Specific Element Influencing Contractile Function

Cited by 95 publications

References 26 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

Sex and Sex Hormone–Dependent Cardiovascular Stress Responses

Mechanisms of Sex Disparities in Cardiovascular Function and Remodeling

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