Foxo1 represses expression of musclin, a skeletal muscle-derived secretory factor.
ABSTRACT 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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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 01/2013; 8(8):e72004. · 3.73 Impact Factor
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ABSTRACT: The musculoskeletal system evolved in mammals to perform diverse functions that include locomotion, facilitating breathing, protecting internal organs, and coordinating global energy expenditure. Bone and skeletal muscles involved with locomotion are both derived from somitic mesoderm and accumulate peak tissue mass synchronously, according to genetic information and environmental stimuli. Aging results in the progressive and parallel loss of bone (osteopenia) and skeletal muscle (sarcopenia) with profound consequences for quality of life. Age-associated sarcopenia results in reduced endurance, poor balance and reduced mobility that predispose elderly individuals to falls, which more frequently result in fracture because of concomitant osteoporosis. Thus, a better understanding of the mechanisms underlying the parallel development and involution of these tissues is critical to developing new and more effective means to combat osteoporosis and sarcopenia in our increasingly aged population. This perspective will highlight recent advances in our understanding of mechanisms coupling bone and skeletal muscle mass, and identify critical areas where further work is needed. © 2013 American Society for Bone and Mineral Research.Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 04/2013; · 6.04 Impact Factor
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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; · 7.55 Impact Factor