The Experts below are selected from a list of 285 Experts worldwide ranked by ideXlab platform
Benoit Viollet - One of the best experts on this subject based on the ideXlab platform.
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Antagonistic control of Muscle Cell size by AMPK and mTORC1.
Cell Cycle, 2011Co-Authors: Rémi Mounier, Louise Lantier, Jocelyne Leclerc, Athanassia Sotiropoulos, Marc Foretz, Benoit ViolletAbstract:Nutrition and physical activity have profound effects on skeletal Muscle metabolism and growth. Regulation of Muscle mass depends on a thin balance between growth-promoting and growth-suppressing factors. Over the past decade, the mammalian target of rapamycin (mTOR) kinase has emerged as an essential factor for Muscle growth by mediating the anabolic response to nutrients, insulin, insulin-like growth factors and resistance exercise. As opposed to the mTOR signaling pathway, the AMP-activated protein kinase (AMPK) is switched on during starvation and endurance exercise to upregulate energy-conserving processes. Recent evidence indicates that mTORC1 (mTOR Complex 1) and AMPK represent two antagonistic forces governing Muscle adaption to nutrition, starvation and growth stimulation. Animal knockout models with impaired mTORC1 signaling showed decreased Muscle mass correlated with increased AMPK activation. Interestingly, AMPK inhibition in p70S6K-deficient Muscle Cells restores Cell growth and sensitivity to nutrients. Conversely, Muscle Cells lacking AMPK have increased mTORC1 activation with increased Cell size and protein synthesis rate. We also demonstrated that the hypertrophic action of MyrAkt is enhanced in AMPK-deficient Muscle, indicating that AMPK acts as a negative feedback control to restrain Muscle hypertrophy. Our recent results extend this notion by showing that AMPKα1, but not AMPKα2, regulates Muscle Cell size through the control of mTORC1 signaling. These results reveal the diverse functions of the two catalytic isoforms of AMPK, with AMPKα1 playing a predominant role in the control of Muscle Cell size and AMPKα2 mediating Muscle metabolic adaptation. Thus, the crosstalk between AMPK and mTORC1 signaling is a highly regulated way to control changes in Muscle growth and metabolic rate imposed by external cues.
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Coordinated maintenance of Muscle Cell size control by AMP-activated protein kinase.
FASEB Journal, 2010Co-Authors: Louise Lantier, Rémi Mounier, Jocelyne Leclerc, Mario Pende, Marc Foretz, Benoit ViolletAbstract:Skeletal Muscle mass is regulated by signaling pathways that govern protein synthesis and Cell proliferation, and the mammalian target of rapamycin (mTOR) plays a key role in these processes. Recent studies suggested the crucial role of AMP-activated protein kinase (AMPK) in the inhibition of protein synthesis and Cell growth. Here, we address the role of AMPK in the regulation of Muscle Cell size in vitro and in vivo. The size of AMPK-deficient myotubes was 1.5-fold higher than for controls. A marked increase in p70S6K Thr(389) and rpS6 Ser-235/236 phosphorylation was observed concomitantly with an up-regulation of protein synthesis rate. Treatment with rapamycin prevented p70S6K phosphorylation and rescued Cell size control in AMPK-deficient Cells. Importantly, myotubes lacking AMPK were resistant to further Cell size increase beyond AMPK deletion alone, as MyrAkt-induced hypertrophy was absent in these Cells. Moreover, in skeletal Muscle-specific deficient AMPKalpha1/alpha2 KO mice, soleus Muscle showed a higher mass with myofibers of larger size and was associated with increased p70S6K and rpS6 phosphorylation. Our results uncover the role of AMPK in the maintenance of Muscle Cell size control and highlight the crosstalk between AMPK and mTOR/p70S6K signaling pathways coordinating a metabolic checkpoint on Cell growth.
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Important role for AMPKalpha1 in limiting skeletal Muscle Cell hypertrophy.
FASEB Journal, 2009Co-Authors: Rémi Mounier, Louise Lantier, Jocelyne Leclerc, Athanassia Sotiropoulos, Mario Pende, Dominique Daegelen, Kei Sakamoto, Marc Foretz, Benoit ViolletAbstract:Activation of AMP-activated protein kinase (AMPK) inhibits protein synthesis through the suppression of the mammalian target of rapamycin complex 1 (mTORC1), a critical regulator of Muscle growth. The purpose of this investigation was to determine the role of the AMPKalpha1 catalytic subunit on Muscle Cell size control and adaptation to Muscle hypertrophy. We found that AMPKalpha1(-/-) primary cultured myotubes and myofibers exhibit larger Cell size compared with control Cells in response to chronic Akt activation. We next subjected the plantaris Muscle of AMPKalpha1(-/-) and control mice to mechanical overloading to induce Muscle hypertrophy. We observed significant elevations of AMPKalpha1 activity in the control Muscle at days 7 and 21 after the overload. Overloading-induced Muscle hypertrophy was significantly accelerated in AMPKalpha1(-/-) mice than in control mice [+32 vs. +53% at day 7 and +57 vs. +76% at day 21 in control vs. AMPKalpha1(-/-) mice, respectively]. This enhanced growth of AMPKalpha1-deficient Muscle was accompanied by increased phosphorylation of mTOR signaling downstream targets and decreased phosphorylation of eukaryotic elongation factor 2. These results demonstrate that AMPKalpha1 plays an important role in limiting skeletal Muscle overgrowth during hypertrophy through inhibition of the mTOR-signaling pathway.
Aiping F. Smith - One of the best experts on this subject based on the ideXlab platform.
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A 310-bp minimal promoter mediates smooth Muscle Cell-specific expression of telokin
2016Co-Authors: Aiping F. Smith, Paul B. Herring, Robert M. Bigsby, Ann R. Word, Aiping FAbstract:smooth Muscle Cell-specific expression of telokin. Am. J
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Telokin expression is mediated by a smooth Muscle Cell-specific promoter
American Journal of Physiology-Cell Physiology, 1996Co-Authors: Aiping F. SmithAbstract:The carboxy terminus of the smooth Muscle myosin light chain kinase (smMLCK) is expressed as an independent protein, telokin. Western and Northern blotting analyses demonstrated that telokin protein and mRNA are expressed at high levels only in adult and embryonic smooth Muscle tissues and Cells. In vitro transfection assays in A10 smooth Muscle Cells identified a functional promoter located in an intron in the 3' region of the smMLCK gene that directs the smooth Muscle Cell-specific transcription of telokin. To test the Cell specificity of the telokin promoter in vivo, transgenic mice were generated in which the telokin promoter was used to drive expression of SV40 large T-antigen. Expression of T-antigen in the transgenic mice paralleled that of the endogenous telokin gene. High levels of T-antigen expression were observed in smooth Muscle tissues of the digestive, urinary, and reproductive tracts, with lower levels of expression in airway and vascular smooth Muscle. Expression was restricted to smooth Muscle Cells, with no expression detected in any other Cell type.
Karsten Schrör - One of the best experts on this subject based on the ideXlab platform.
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platelet derived microparticles stimulate coronary artery smooth Muscle Cell mitogenesis by a pdgf independent mechanism
Thrombosis Research, 2000Co-Authors: Artur-aron Weber, Hermann Oliver Koppen, Karsten SchrörAbstract:This study investigates the role of platelet-derived microparticles for vascular smooth Muscle Cell (SMC) proliferation. Microparticles concentration dependently stimulated p42/p44 MAP kinase phosphorylation, c-fos induction, DNA synthesis, and proliferation of cultured bovine coronary artery SMC. The maximum mitogenic effects of microparticles were significantly higher than those of platelet-derived growth factor (PDGF)-BB. Microparticle-induced SMC mitogenesis was heat sensitive, whereas the effects of PDGF were not. In addition, neutralizing anti-PDGF antibodies prevented PDGF-induced DNA synthesis but did not inhibit the effects of microparticles. In contrast to PDGF, which potently stimulated SMC migration, microparticles had only minor migratory activity. These results demonstrate a novel mechanism of SMC mitogenesis by platelet-derived microparticles that is probably independent of PDGF.
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Cyclooxygenase-independent inhibition of smooth Muscle Cell mitogenesis by ibuprofen.
European journal of pharmacology, 2000Co-Authors: Artur-aron Weber, Hakan Yildirim, Karsten SchrörAbstract:The aryl-propionic acid derivative, ketoprofen, has been shown to inhibit fibroblast growth by a cylooxygenase-dependent mechanism [Sanchez, T., Moreno, J.J., 1999. S(+) enantiomer inhibits prostaglandin production and Cell growth in 3T6 fibroblast cultures. Eur. J. Pharmacol. 370, 63-67]. The present study demonstrates that ibuprofen, another aryl-propionic acid derivative, inhibited platelet-derived growth factor-BB (20 ng/ml)-induced mitogenesis of cultured bovine coronary artery smooth Muscle Cells in a stereo-independent manner. In addition, pretreatment of the Cells with indomethacin (3 microM) did not affect the inhibitory effects of ibuprofen enantiomers on smooth Muscle Cell mitogenesis. Thus, aryl-propionic acid-type cyclooxygenase inhibitors can inhibit Cell proliferation by both, cyclooxygenase-dependent and -independent ways.
Cecilia M Giachelli - One of the best experts on this subject based on the ideXlab platform.
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Smooth Muscle Cell phenotypic transition associated with calcification: Upregulation of Cbfa1 and downregulation of smooth Muscle lineage markers
Circulation Research, 2001Co-Authors: Susie A. Steitz, Gilles Karsenty, Gabrielle Curinga, Hsueh Ying Yang, Paul Haynes, Mei Y Speer, Thorsten Schinke, Ruedi Aebersold, Cecilia M GiachelliAbstract:Bovine aortic smooth Muscle Cell (BASMC) cultures undergo mineralization on addition of the organic phosphate donor, beta-glycerophosphate (betaGP). Mineralization is characterized by apatite deposition on collagen fibrils and the presence of matrix vesicles, as has been described in calcified vascular lesions in vivo as well as in bone and teeth. In the present study, we used this model to investigate the molecular mechanisms driving vascular calcification. We found that BASMCs lost their lineage markers, SM22alpha and smooth Muscle alpha-actin, within 10 days of being placed under calcifying conditions. Conversely, the Cells gained an osteogenic phenotype as indicated by an increase in expression and DNA-binding activity of the transcription factor, core binding factor alpha1 (Cbfa1). Moreover, genes containing the Cbfa1 binding site, OSE2, including osteopontin, osteocalcin, and alkaline phosphatase were elevated. The relevance of these in vitro findings to vascular calcification in vivo was further studied in matrix GLA protein null (MGP(-/-)) mice whose arteries spontaneously calcify. We found that arterial calcification was associated with a similar loss in smooth Muscle markers and a gain of osteopontin and Cbfa1 expression. These data demonstrate a novel association of vascular calcification with smooth Muscle Cell phenotypic transition, in which several osteogenic proteins including osteopontin, osteocalcin, and the bone determining factor Cbfa1 are gained. The findings suggest a positive role for SMCs in promoting vascular calcification.
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phosphate regulation of vascular smooth Muscle Cell calcification
Circulation Research, 2000Co-Authors: Shuichi Jono, Marc D Mckee, Charles E Murry, Atsushi Shioi, Yoshiki Nishizawa, Katsuhito Mori, Hirotoshi Morii, Cecilia M GiachelliAbstract:Abstract —Vascular calcification is a common finding in atherosclerosis and a serious problem in diabetic and uremic patients. Because of the correlation of hyperphosphatemia and vascular calcification, the ability of extraCellular inorganic phosphate levels to regulate human aortic smooth Muscle Cell (HSMC) culture mineralization in vitro was examined. HSMCs cultured in media containing normal physiological levels of inorganic phosphate (1.4 mmol/L) did not mineralize. In contrast, HSMCs cultured in media containing phosphate levels comparable to those seen in hyperphosphatemic individuals (>1.4 mmol/L) showed dose-dependent increases in mineral deposition. Mechanistic studies revealed that elevated phosphate treatment of HSMCs also enhanced the expression of the osteoblastic differentiation markers osteocalcin and Cbfa-1. The effects of elevated phosphate on HSMCs were mediated by a sodium-dependent phosphate cotransporter (NPC), as indicated by the ability of the specific NPC inhibitor phosphonoformic acid, to dose dependently inhibit phosphate-induced calcium deposition as well as osteocalcin and Cbfa-1 gene expression. With the use of polymerase chain reaction and Northern blot analyses, the NPC in HSMCs was identified as Pit-1 (Glvr-1), a member of the novel type III NPCs. These data suggest that elevated phosphate may directly stimulate HSMCs to undergo phenotypic changes that predispose to calcification and offer a novel explanation of the phenomenon of vascular calcification under hyperphosphatemic conditions. The full text of this article is available at http://www.circresaha.org.
Rémi Mounier - One of the best experts on this subject based on the ideXlab platform.
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Antagonistic control of Muscle Cell size by AMPK and mTORC1.
Cell Cycle, 2011Co-Authors: Rémi Mounier, Louise Lantier, Jocelyne Leclerc, Athanassia Sotiropoulos, Marc Foretz, Benoit ViolletAbstract:Nutrition and physical activity have profound effects on skeletal Muscle metabolism and growth. Regulation of Muscle mass depends on a thin balance between growth-promoting and growth-suppressing factors. Over the past decade, the mammalian target of rapamycin (mTOR) kinase has emerged as an essential factor for Muscle growth by mediating the anabolic response to nutrients, insulin, insulin-like growth factors and resistance exercise. As opposed to the mTOR signaling pathway, the AMP-activated protein kinase (AMPK) is switched on during starvation and endurance exercise to upregulate energy-conserving processes. Recent evidence indicates that mTORC1 (mTOR Complex 1) and AMPK represent two antagonistic forces governing Muscle adaption to nutrition, starvation and growth stimulation. Animal knockout models with impaired mTORC1 signaling showed decreased Muscle mass correlated with increased AMPK activation. Interestingly, AMPK inhibition in p70S6K-deficient Muscle Cells restores Cell growth and sensitivity to nutrients. Conversely, Muscle Cells lacking AMPK have increased mTORC1 activation with increased Cell size and protein synthesis rate. We also demonstrated that the hypertrophic action of MyrAkt is enhanced in AMPK-deficient Muscle, indicating that AMPK acts as a negative feedback control to restrain Muscle hypertrophy. Our recent results extend this notion by showing that AMPKα1, but not AMPKα2, regulates Muscle Cell size through the control of mTORC1 signaling. These results reveal the diverse functions of the two catalytic isoforms of AMPK, with AMPKα1 playing a predominant role in the control of Muscle Cell size and AMPKα2 mediating Muscle metabolic adaptation. Thus, the crosstalk between AMPK and mTORC1 signaling is a highly regulated way to control changes in Muscle growth and metabolic rate imposed by external cues.
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Coordinated maintenance of Muscle Cell size control by AMP-activated protein kinase.
FASEB Journal, 2010Co-Authors: Louise Lantier, Rémi Mounier, Jocelyne Leclerc, Mario Pende, Marc Foretz, Benoit ViolletAbstract:Skeletal Muscle mass is regulated by signaling pathways that govern protein synthesis and Cell proliferation, and the mammalian target of rapamycin (mTOR) plays a key role in these processes. Recent studies suggested the crucial role of AMP-activated protein kinase (AMPK) in the inhibition of protein synthesis and Cell growth. Here, we address the role of AMPK in the regulation of Muscle Cell size in vitro and in vivo. The size of AMPK-deficient myotubes was 1.5-fold higher than for controls. A marked increase in p70S6K Thr(389) and rpS6 Ser-235/236 phosphorylation was observed concomitantly with an up-regulation of protein synthesis rate. Treatment with rapamycin prevented p70S6K phosphorylation and rescued Cell size control in AMPK-deficient Cells. Importantly, myotubes lacking AMPK were resistant to further Cell size increase beyond AMPK deletion alone, as MyrAkt-induced hypertrophy was absent in these Cells. Moreover, in skeletal Muscle-specific deficient AMPKalpha1/alpha2 KO mice, soleus Muscle showed a higher mass with myofibers of larger size and was associated with increased p70S6K and rpS6 phosphorylation. Our results uncover the role of AMPK in the maintenance of Muscle Cell size control and highlight the crosstalk between AMPK and mTOR/p70S6K signaling pathways coordinating a metabolic checkpoint on Cell growth.
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Important role for AMPKalpha1 in limiting skeletal Muscle Cell hypertrophy.
FASEB Journal, 2009Co-Authors: Rémi Mounier, Louise Lantier, Jocelyne Leclerc, Athanassia Sotiropoulos, Mario Pende, Dominique Daegelen, Kei Sakamoto, Marc Foretz, Benoit ViolletAbstract:Activation of AMP-activated protein kinase (AMPK) inhibits protein synthesis through the suppression of the mammalian target of rapamycin complex 1 (mTORC1), a critical regulator of Muscle growth. The purpose of this investigation was to determine the role of the AMPKalpha1 catalytic subunit on Muscle Cell size control and adaptation to Muscle hypertrophy. We found that AMPKalpha1(-/-) primary cultured myotubes and myofibers exhibit larger Cell size compared with control Cells in response to chronic Akt activation. We next subjected the plantaris Muscle of AMPKalpha1(-/-) and control mice to mechanical overloading to induce Muscle hypertrophy. We observed significant elevations of AMPKalpha1 activity in the control Muscle at days 7 and 21 after the overload. Overloading-induced Muscle hypertrophy was significantly accelerated in AMPKalpha1(-/-) mice than in control mice [+32 vs. +53% at day 7 and +57 vs. +76% at day 21 in control vs. AMPKalpha1(-/-) mice, respectively]. This enhanced growth of AMPKalpha1-deficient Muscle was accompanied by increased phosphorylation of mTOR signaling downstream targets and decreased phosphorylation of eukaryotic elongation factor 2. These results demonstrate that AMPKalpha1 plays an important role in limiting skeletal Muscle overgrowth during hypertrophy through inhibition of the mTOR-signaling pathway.
