Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.22 (cdc2)
 8,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Myostatin, a member of the transforming growth factor-beta (TGF-beta) superfamily, has been shown to be a negative regulator of myogenesis. Here we show that myostatin functions by controlling the proliferation of muscle precursor cells. When C(2)C(12) myoblasts were incubated with myostatin, proliferation of myoblasts decreased with increasing levels of myostatin. Fluorescence-activated cell sorting analysis revealed that myostatin prevented the progression of myoblasts from the G(1)- to S-phase of the cell cycle. Western analysis indicated that myostatin specifically up-regulated p21(Waf1, Cip1), a cyclin-dependent kinase inhibitor, and decreased the levels and activity of Cdk2 protein in myoblasts. Furthermore, we also observed that in myoblasts treated with myostatin protein, Rb was predominately present in the hypophosphorylated form. These results suggests that, in response to myostatin signaling, there is an increase in p21 expression and a decrease in Cdk2 protein and activity thus resulting in an accumulation of hypophosphorylated Rb protein. This, in turn, leads to the arrest of myoblasts in G(1)-phase of cell cycle. Thus, we propose that the generalized muscular hyperplasia phenotype observed in animals that lack functional myostatin could be as a result of deregulated myoblast proliferation.
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PMID:Myostatin, a negative regulator of muscle growth, functions by inhibiting myoblast proliferation. 1097 4

Satellite cells are quiescent muscle stem cells that promote postnatal muscle growth and repair. Here we show that myostatin, a TGF-beta member, signals satellite cell quiescence and also negatively regulates satellite cell self-renewal. BrdU labeling in vivo revealed that, among the Myostatin-deficient satellite cells, higher numbers of satellite cells are activated as compared with wild type. In contrast, addition of Myostatin to myofiber explant cultures inhibits satellite cell activation. Cell cycle analysis confirms that Myostatin up-regulated p21, a Cdk inhibitor, and decreased the levels and activity of Cdk2 protein in satellite cells. Hence, Myostatin negatively regulates the G1 to S progression and thus maintains the quiescent status of satellite cells. Immunohistochemical analysis with CD34 antibodies indicates that there is an increased number of satellite cells per unit length of freshly isolated Mstn-/- muscle fibers. Determination of proliferation rate suggests that this elevation in satellite cell number could be due to increased self-renewal and delayed expression of the differentiation gene (myogenin) in Mstn-/- adult myoblasts. Taken together, these results suggest that Myostatin is a potent negative regulator of satellite cell activation and thus signals the quiescence of satellite cells.
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PMID:Myostatin negatively regulates satellite cell activation and self-renewal. 1296 5

Rhabdomyosarcoma (RMS) tumors are the most common soft-tissue sarcomas in childhood. In this investigation, we show that myostatin, a skeletal muscle-specific inhibitor of growth and differentiation is expressed and translated in the cultured RMS cell line, RD. The addition of exogenous recombinant myostatin inhibits the proliferation of RD cells cultured in growth media, consistent with the role of myostatin in normal myoblast proliferation inhibition. However, unlike normal myoblasts, upregulation of p21 was not observed. Rather, myostatin signalling resulted in the specific downregulation of both Cdk2 and its cognate partner, cyclin-E. The analysis of Rb reveals that there was no change in its phosphorylation status with myostatin treatment, consistent with D-type-cyclin-Cdk4/6 complexes being active in the absence of p21. Moreover, the activity of Rb appeared to be unchanged between treated and nontreated RD cells, as determined by the ability of Rb to bind E2F1. The examination of NPAT, a substrate of cyclin-E-Cdk2 involved in the transcriptional activation of replication-dependent histone gene expression, revealed that it undergoes a loss of phosphorylation with myostatin treatment. Supporting this, a downregulation in H4-histone gene expression was observed. These results suggest that myostatin could potentially be used as an inhibitor of RMS proliferation and define a previously uncharacterized, Rb-independent mechanism for the inhibition of muscle precursor cell proliferation by myostatin.
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PMID:Myostatin inhibits rhabdomyosarcoma cell proliferation through an Rb-independent pathway. 1472 80

Myostatin (Mst) is a negative regulator of skeletal muscle in humans and animals. It is moderately expressed in the heart of sheep and cattle, increasing considerably after infarction. Genetic blockade of Mst expression increases cardiomyocyte growth. We determined whether Mst overexpression in the heart of transgenic mice reduces left ventricular size and function, and inhibits in vitro cardiomyocyte proliferation. Young transgenic mice overexpressing Mst in the heart (Mst transgenic mice (TG) under a muscle creatine kinase (MCK) promoter active in cardiac and skeletal muscle, and Mst knockout (Mst (-/-)) mice were used. Xiscan angiography revealed that the left ventricular ejection fraction did not differ between the Mst TG and the Mst (-/-) mice, when compared with their respective wild-type strains, despite the decrease in whole heart and left ventricular size in Mst TG mice, and their increase in Mst (-/-) animals. The expected changes in cardiac Mst were measured by RT-PCR and western blot. Mst and its receptor (ActRIIb) were detected by RT-PCR in rat H9c2 cardiomyocytes. Transfection of H9c2 with plasmids expressing Mst under muscle-specific creatine kinase promoter, or cytomegalovirus promoter, enhanced p21 and reduced cdk2 expression, when assessed by western blot. A decrease in cell number occurred by incubation with recombinant Mst (formazan assay), without affecting apoptosis or cardiomyocyte size. Anti-Mst antibody increased cardiomyocyte replication, whereas transfection with the Mst-expressing plasmids inhibited it. In conclusion, Mst does not affect cardiac systolic function in mice overexpressing or lacking the active protein, but it reduces cardiac mass and cardiomyocyte proliferation.
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PMID:Alterations in myostatin expression are associated with changes in cardiac left ventricular mass but not ejection fraction in the mouse. 1759 22

Myostatin decreases muscle mass and this is accomplished, in part, by inhibiting muscle satellite cell proliferation and differentiation by regulating the expression of cell cycle-related proteins (e.g. p21 and cdk2) and myogenic regulatory factors (e.g. myogenin and MyoD). The purpose of this investigation was to determine whether protein ingestion before and after a resistance exercise (RE) bout affects myostatin and cell cycle-related gene expression. Strength-trained middle-aged to older men were divided into a protein group (61.4 +/- 4.3 years, n = 9) or a placebo group (62.1 +/- 4.2 years, n = 9). Muscle biopsies from the vastus lateralis muscle were taken at rest and 1 and 48 h after a 5 x 10 repetition leg press RE bout. Protein (15 g whey) or non-caloric placebo was taken immediately before and after the RE bout. mRNA expression levels of myostatin and related genes (AcvrIIb, FLRG, p21, p27, cdk2, myogenin and MyoD) were determined by Taqman probe-based real-time RT-PCR and normalized to GAPDH mRNA. Myostatin mRNA decreased after a RE bout, but only in the placebo group (P < or = 0.05). Conversely, myostatin-binding protein FLRG and cell-cycle kinase cdk2 mRNA increased only in the protein group (P < or = 0.05). p21 mRNA was increased at 1 h post-RE in placebo (P < or = 0.05) and tended to be increased in the protein group (P = 0.08). Myostatin, its binding protein and cell cycle-related gene expressions are affected by single RE bout and these responses are further modified by whey protein intake. Therefore, controlling nutrition intake is important when studying gene expression responses to exercise.
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PMID:The effects of whey protein on myostatin and cell cycle-related gene expression responses to a single heavy resistance exercise bout in trained older men. 1792 33

The existence of skeletal muscle-derived stem cells (MDSCs) has been suggested in mammals; however, the signaling pathways controlling MDSC proliferation remain largely unknown. Here we report the isolation of myosphere-derived progenitor cells (MDPCs) that can give rise to beating cardiomyocytes from adult skeletal muscle. We identified that follistatin, an antagonist of TGF-beta family members, was predominantly expressed in MDPCs, whereas myostatin was mainly expressed in myogenic cells and mature skeletal muscle. Although follistatin enhanced the replicative growth of MDPCs through Smad2/3 inactivation and cell cycle progression, disruption of myostatin did not increase the MDPC proliferation. By contrast, inhibition of activin A (ActA) or growth differentiation factor 11 (GDF11) signaling dramatically increased MDPC proliferation via down-regulation of p21 and increases in the levels of cdk2/4 and cyclin D1. Thus, follistatin may be an effective progenitor-enhancing agent neutralizing ActA and GDF11 signaling to regulate the growth of MDPCs in skeletal muscle.
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PMID:Skeletal muscle-derived progenitors capable of differentiating into cardiomyocytes proliferate through myostatin-independent TGF-beta family signaling. 1804 32

The effects of timed ingestion of high-quality protein before and after resistance exercise are not well known. In this study, young men were randomized to protein (n = 11), placebo (n = 10) and control (n = 10) groups. Muscle cross-sectional area by MRI and muscle forces were analyzed before and after 21 weeks of either heavy resistance training (RT) or control period. Muscle biopsies were taken before, and 1 and 48 h after 5 x 10 repetition leg press exercise (RE) as well as 21 weeks after RT. Protein (15 g of whey both before and after exercise) or non-energetic placebo were provided to subjects in the context of both single RE bout (acute responses) as well as each RE workout twice a week throughout the 21-week-RT. Protein intake increased (P < or = 0.05) RT-induced muscle cross-sectional area enlargement and cell-cycle kinase cdk2 mRNA expression in the vastus lateralis muscle suggesting higher proliferating cell activation response with protein supplementation. Moreover, protein intake seemed to prevent 1 h post-RE decrease in myostatin and myogenin mRNA expression but did not affect activin receptor IIb, p21, FLRG, MAFbx or MyoD expression. In conclusion, protein intake close to resistance exercise workout may alter mRNA expression in a manner advantageous for muscle hypertrophy.
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PMID:Acute and long-term effects of resistance exercise with or without protein ingestion on muscle hypertrophy and gene expression. 1866 Dec 58