Foxo1 represses expression of musclin, a skeletal muscle-derived secretory factor

Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan.
Biochemical and Biophysical Research Communications (Impact Factor: 2.3). 01/2008; 364(2):358-65. DOI: 10.1016/j.bbrc.2007.10.013
Source: PubMed


Musclin is a novel skeletal muscle-derived secretory factor, whose mRNA level is markedly regulated by nutritional status. In the present study, we investigated the mechanism of musclin mRNA regulation by insulin. In C2C12 myocytes, insulin-induced upregulation of musclin mRNA was significantly decreased by treatment of phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002, and was abolished in C2C12 myocytes stably expressing a constitutively active Foxo1 (Foxo1-3A), suggesting the involvement of Foxo1 in the regulation of musclin mRNA. Promoter deletion analysis of musclin promoter revealed that the region of -303/-123 is important for the repression of promoter activity by Foxo1. Chromatin immunoprecipitation assay showed that Foxo1 bound to musclin promoter. Musclin mRNA level was markedly downregulated in gastrocnemius muscle of Foxo1 transgenic mice. Our results demonstrated that Foxo1 downregulates musclin mRNA expression both in vitro and in vivo, which should explain insulin-mediated upregulation of this gene in muscle cells.

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    • "In addition, we used the ab14355 anti-NPR-C antibody to abolish the vasoconstriction caused by musclin in order to highlight the mediation of NPR-C. The first (88LDRL91) and second (117MDRI120) NP-homologous regions of musclin are responsible for the cooperative high-affinity binding to NPR-C [3]. The binding of musclin with NPR-C has been demonstrated by assessing the competition with ANP [3]. "
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    ABSTRACT: Musclin is a novel skeletal muscle-derived secretory factor found in the signal sequence trap of mouse skeletal muscle cDNAs. Musclin possesses a region homologous to the natriuretic peptide family. Thus, musclin is found to bind with the natriuretic peptide clearance receptors. However, the role of musclin in vascular regulation remains unclear. In this study, we aim to investigate the direct effect of musclin on vascular tone and to analyze its role in hypertension using the spontaneously hypertensive rats (SHR). In aortic strips isolated from SHR, musclin induced contractions in a dose-dependent manner. We found that the musclin-induced vasoconstriction was more marked in SHR than in normal rats (WKY). Moreover, this contraction was reduced by blockade of natriuretic peptide receptor C using the ab14355 antibody. Therefore, mediation of the natriuretic peptide receptor in musclin-induced vasoconstriction can be considered. In addition, similar to the natriuretic peptide receptor, expression of the musclin gene in blood vessels was higher in SHR than in WKY. Injection of musclin markedly increased the blood pressure in rats that can be inhibited by anti-musclin antibodies. Musclin-induced vasoconstriction was more pronounced in SHR than in WKY as in its expression. Taken together, these results suggest that musclin is involved in blood pressure regulation. The higher expression of musclin in hypertension indicates that musclin could be used as a new target for the treatment of hypertension in the future.
    PLoS ONE 08/2013; 8(8):e72004. DOI:10.1371/journal.pone.0072004 · 3.23 Impact Factor
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    • "Nutrients and nutrient-sensing pathways also regulate the expression of some myokines. For example, the expression of musclin, a myokine almost exclusively expressed in skeletal muscles, is induced by insulin (Nishizawa et al., 2004) and repressed by the nutrient-and stress-sensing transcription factor FoxO1 (Yasui et al., 2007). Musclin reduces glucose uptake and glycogen synthesis in muscles and may contribute to the development of insulin resistance (Nishizawa et al., 2004). "
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    ABSTRACT: Epidemiological studies in humans suggest that skeletal muscle aging is a risk factor for the development of several age-related diseases such as metabolic syndrome, cancer, Alzheimer's disease, and Parkinson's disease. Here we review recent studies in mammals and Drosophila highlighting how nutrient- and stress-sensing in skeletal muscle can influence lifespan and overall aging of the organism. In addition to exercise and indirect effects of muscle metabolism, growing evidence suggests that muscle-derived growth factors and cytokines, known as myokines, modulate systemic physiology. Myokines may influence the progression of age-related diseases and contribute to the inter-tissue communication that underlies systemic aging. This article is protected by copyright. All rights reserved.
    Aging cell 06/2013; 12(6). DOI:10.1111/acel.12126 · 6.34 Impact Factor
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    • "The function of musclin has been described as responsive to insulin in vivo and inducing insulin resistance in vitro [6, 7]. Furthermore, musclin is also known as a bone-active molecule that is highly expressed in cells of the osteoblast lineage of animals [5, 8]. "
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    ABSTRACT: Musclin is a novel skeletal muscle-derived factor found in the signal sequence trap of mouse skeletal muscle cDNAs. Recently, it has been demonstrated that musclin is involved in the pathogenesis of spontaneously hypertensive rats (SHRs). However, it is known as a genetic hypertension model. In the present study, we aim to investigate the role of musclin in another animal model of hypertension and characterize the direct effect of musclin on vascular contraction. The results show that expression of musclin was increased in arterial tissues isolated from DOCA-salt induced hypertensive rats or the normal rats received repeated vasoconstriction with phenylephrine. Additionally, direct incubation with phenylephrine did not modify the expression of musclin in the in vitro studies. Also, the direct effect of musclin on the increase of intracellular calcium was observed in a concentration-dependent manner. These results provide the evidence to support that musclin is involved in hypertension. Thus, musclin is suitable to be considered as a novel target for treatment of hypertension.
    01/2013; 2013:354348. DOI:10.1155/2014/354348
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