Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin and IGFs are potent inducers of skeletal muscle differentiation. Although PI3K is known to be involved in skeletal muscle differentiation, its downstream targets in this process are not clearly defined. We investigated the roles of Akt and mammalian target of rapamycin (mTOR) in skeletal muscle differentiation. LY294002, a pharmacological inhibitor of PI3K, and the immunosuppressant rapamycin inhibited insulin-induced differentiation of C2C12 myoblasts. LY294002 and rapamycin suppressed myosin heavy chain expression and myotube formation. Transient reporter assays showed that both inhibitors repress muscle creatine kinase (MCK) and myogenin gene transcription. Heterologous expression of Akt1/PKB(alpha) potently suppressed MCK gene transcription without affecting myogenin gene transcription, whereas heterologous expression of Akt2 increased myogenin and MCK gene transcription. Finally, overexpression of myogenin rescued the inhibitory effect of rapamycin on MCK gene transcription, whereas it failed to rescue the inhibitory effect of LY294002 and Akt1. These results suggest that insulin regulates myogenic differentiation chiefly at the level of myogenin gene transcription via PI3K and mTOR. PI3K activity, but not mTOR, may regulate transcriptional activity of myogenin. Our data also suggest that Akt1 and Akt2 play distinct roles in myogenic differentiation.
 ...
PMID:Akt1 and Akt2 differently regulate muscle creatine kinase and myogenin gene transcription in insulin-induced differentiation of C2C12 myoblasts. 1186 3

N(6)-methyl-2(')-deoxyadenosine (MedAdo) is a nucleoside naturally found in prokaryotic DNA. Interestingly, the N(6)-methylation of adenine in DNA seems to have been counter-selected during the course of evolution since MedAdo has not been detected in mammalian DNA until now. We show here that treatment with MedAdo induces myogenesis in C2C12 myoblasts. The presence of MedAdo in C2C12 DNA was investigated using a method based on HPLC coupled to electrospray ionization tandem mass spectrometry which is several thousand fold more sensitive than assays used previously. By this procedure, MedAdo is detected in the DNA from MedAdo-treated cells but remains undetectable in the DNA from control cells. Furthermore, MedAdo regulates the expression of p21, myogenin, mTOR, and MHC. Interestingly, in the pluripotent C2C12 cell line, MedAdo drives the differentiation towards myogenesis only. Thus, the biological effect of MedAdo is suppressed in the presence of BMP-2 which transdifferentiates C2C12 from myogenic into osteogenic lineage cells. Taken together these results point to MedAdo as a novel inducer of myogenesis and further extends the differentiation potentialities of this methylated nucleoside. Furthermore, these data raise the intriguing possibility that the biological effects of MedAdo on cell differentiation may have led to its counter-selection in eukaryotes.
 ...
PMID:N(6)-Methyldeoxyadenosine, a nucleoside commonly found in prokaryotes, induces C2C12 myogenic differentiation. 1473 30

Cdk5 regulates myogenesis but the signaling cascade through which Cdk5 modulates this process remains to be characterized. Here, we investigated whether PI3K, Akt, p70S6K, p38 MAPK, p44/42 MAPK, and Egr-1 serve as upstream regulators of Cdk5 during L6 myoblast differentiation. Upon serum reduction, we found that besides elevated expression of Cdk5 and its activator, p35, and increased Cdk5/p35 activity, Egr-1, Akt, p70S6K, and p38 MAPK activity were upregulated in differentiating L6 cells. However, p44/42 MAPK was downregulated and SAPK/JNK was unaffected. LY294002, a PI3K inhibitor, blocked the activation of Akt and p70S6K, indicating that Akt and p70S6K activation is linked to PI3K activation. The lack of LY294002 effect on p38 MAPK suggests that p38 MAPK activation is not associated with PI3K activation. Rapamycin, a specific inhibitor of FRAP/mTOR (the upstream kinase of p70S6K), also blocked p70S6K activation, indicating the involvement of FRAP/mTOR activation. LY294002 and rapamycin also blocked the enhancement of Egr-1 level, Cdk5 activity, and myogenin expression, suggesting that upregulation of these factors is coupled to PI3K-p70S6K activation. Overexpression of dominant-negative-Akt also reduced Cdk5/p35 activity and myogenin expression, indicating that the PI3K-p70S6K-Egr-1-Cdk5 signaling cascade is linked to Akt activation. SB2023580, a p38 MAPK inhibitor, had no effect on p70S6K, Egr-1, or Cdk5 activity, suggesting that p38 MAPK activation lies in a pathway distinct from the PI3K-Akt-p70S6K-Egr-1 pathway that we identify as the upstream modulator of Cdk5 activity during L6 myoblast differentiation.
 ...
PMID:L6 myoblast differentiation is modulated by Cdk5 via the PI3K-AKT-p70S6K signaling pathway. 1520 59

The high mobility group type A-2 (HMGA 2) transcription factor is involved in proliferation and differentiation, mainly during embryogenesis. Its activated form (HMGA 2/T) presents oncogenic activities both in vivo and in vitro. However, its precise role during embryogenesis is unknown. We investigated its role during the commitment of mouse embryonic stem (ES) cells by constructing cell lines expressing either wild type (wt) or HMGA 2/T forms of the gene. Following differentiation, control and wt HMGA 2 ES cells did not display myotubes; whereas HMGA 2/T ES cell lines massively formed contractile myotubes. Furthermore, as opposed to control cells, HMGA 2/T ES cells highly expressed the muscle myosin heavy chain (MHC) marker. Interestingly, in experimental conditions inhibitory for myogenesis, we observed a strong expression of MyoD and myogenin in HMGA 2/T cells. By contrast, commitment into adipocyte, neuron, and cardiomyocyte lineages was not affected. Teratocarcinomas induced by HMGA 2/T ES cell lines presented numerous skeletal muscle-differentiated tissues that were not observed in wt HMGA 2 or control tumours. Finally, rapamycin, an inhibitor of the mTOR kinase, downregulated endogenous HMGA-2 expression and inhibited myogenesis. This effect was prevented by overexpression of exogenous HMGA-2. Our results reveal a novel function of HMGA-2 in skeletal muscle differentiation.
 ...
PMID:A new role for the oncogenic high-mobility group A2 transcription factor in myogenesis of embryonic stem cells. 1600 98

Skeletal myogenesis is a well orchestrated cascade of events regulated by multiple signaling pathways, one of which is recently characterized by its sensitivity to the bacterial macrolide rapamycin. Previously we reported that the mammalian target of rapamycin (mTOR) regulates the initiation of the differentiation program in mouse C2C12 myoblasts by controlling the expression of insulin-like growth factor-II in a kinase-independent manner. Here we provide experimental evidence suggesting that a different mode of mTOR signaling regulates skeletal myogenesis at a later stage. In the absence of endogenous mTOR function in C2C12 cells treated with rapamycin, a kinase-inactive mTOR fully supports myogenin expression, but causes a delay in contractile protein expression. Myoblasts fuse to form nascent myotubes in the absence of kinase-active mTOR, whereas the formation of mature myotubes by further fusion requires the catalytic activity of mTOR. Therefore, the two stages of myocyte fusion are molecularly separable at the level of mTOR signaling. In addition, our data suggest that a factor secreted into the culture medium is responsible for mediating the function of mTOR in regulating the late-stage fusion leading to mature myotubes. Furthermore, taking advantage of the unique features of cells stably expressing a mutant mTOR, we have performed cDNA microarray analysis to compare global gene expression profiles between mature and nascent myotubes, the results of which have implicated classes of genes and revealed candidate regulators in myotube maturation or functions of mature myotubes.
 ...
PMID:Mammalian target of rapamycin (mTOR) signaling is required for a late-stage fusion process during skeletal myotube maturation. 1604 80

Alveolar rhabdomyosarcoma (RMS) has a much poorer outcome than embryonal RMS. In this study, we found that IGF-I affected the induction of myogenin and cell cycle progression in alveolar RMS cells, but not in embryonal RMS cells. IGF-I enhanced the induction of myogenin protein in alveolar RMS SJ-Rh30 and KP-RMS-MS cells as it did in myoblast C2C12 cells, but not in embryonal RMS RD or KP-RMS-KH cells. IGF-I induction of myogenin protein was blocked by anti-IGF-IR monoclonal antibody alphaIR-3 and the mTOR-specific inhibitor rapamycin. In Rh30mTOR-rr cells, which stably express a rapamycin-resistant mutant mTOR, rapamycin did not inhibit IGF-I induction of myogenin protein. These data suggest that IGF-I induces myogenin in alveolar RMS cells through the IGF-IR/mTOR pathway. In C2C12 cells, IGF-I induces myogenin protein followed by cell cycle arrest leading to myogenic differentiation. IGF-I promoted G1-S cell cycle progression without any signs of terminal differentiation in alveolar RMS cells. On the other hand, IGF-I promoted neither cell cycle arrest nor G1-S cell cycle progression in embryonal RMS cells. In alveolar RMS SJ-Rh30 cells, 4E-BP1, one of two effectors downstream of mTOR, was continuously hyperphosphorylated by IGF-I, whereas in embryonal RMS RD cells, 4E-BP1 was only transiently hyperphosphorylated. These findings suggest that the different effects of IGF-I on myogenin induction and cell cycle progression in alveolar and embryonal RMS cells are due to a difference of phosphorylation status of 4E-BP1. These different responses to IGF-I help to explain immunohistochemical and clinical behavioral differences between alveolar and embryonal RMS.
 ...
PMID:Insulin-like growth factor-I has different effects on myogenin induction and cell cycle progression in human alveolar and embryonal rhabdomyosarcoma cells. 1754 3

Variation in ACE activity affects myogenic differentiation in C2C12 cells. The present study investigated the mechanism by which ACE influences the myogenic differentiation using the ACE-transduced C2C12 cells. Overexpression of ACE induced the down-regulation of myosin heavy chain, a late myogenic marker at 3-5 days after induction of differentiation. ACE-transduced cells exhibited the immature myotubes but an early myogenic marker (myogenin) was transiently increased at day 1. In ACE-transduced cells, phosphorylation of mTOR and its downstream effector (p70S6K) was suppressed at 2-5 day. However, upstream effector of mTOR (Akt) was transiently suppressed at day 3. Expression of IGF-II mRNA, which is controlled by mTOR, was also down-regulated during the differentiation in ACE-transduced cells. On the other hand, the treatment of cells with captopril, an ACE inhibitor, induced up-regulations of myosin heavy chain and phosphorylated p70S6K. These results suggest that ACE negatively regulates the myotube maturation via impairment of mTOR function.
 ...
PMID:ACE activity affects myogenic differentiation via mTOR signaling. 1789 57

This study compared the effects of leucine and glutamine on the mTOR pathway, on protein synthesis and on muscle-specific gene expression in myogenic C(2)C(12) cells. Leucine increased the phosphorylation state of mTOR, on both Ser2448 and Ser2481, and its downstream effectors, p70(S6k), S6 and 4E-BP1. By contrast, glutamine decreased the phosphorylation state of mTOR on Ser2448, p70(S6k) and 4E-BP1, but did not modify the phosphorylation state of mTOR on Ser2481 and S6. Whilst the phosphorylation state of the mTOR pathway is usually related to protein synthesis, the incorporation of labelled methionine/cysteine was only transiently modified by leucine and was unaltered by glutamine. However, these two amino acids affected the mRNA levels of desmin, myogenin and myosin heavy chain in a time-dependant manner. In conclusion, leucine and glutamine have opposite effects on the mTOR pathway. Moreover, they induce modification of muscle-specific gene expression, unrelated to their effects on the mTOR/p70(S6k) pathway.
 ...
PMID:Antagonistic effects of leucine and glutamine on the mTOR pathway in myogenic C2C12 cells. 1797 88

Muscle growth is associated with an activation of the mTOR signaling pathway and satellite cell regulators. The purpose of this study was to determine whether 17 selected genes associated with mTOR/muscle protein synthesis and the satellite cells/myogenic program are differentially expressed in young and older human skeletal muscle at rest and in response to a potent anabolic stimulus [resistance exercise + essential amino acid ingestion (RE+EAA)]. Twelve male subjects (6 young, 6 old) completed a bout of heavy resistance exercise. Muscle biopsies were obtained before and at 3 and 6 h post RE+EAA. Subjects ingested leucine-enriched essential amino acids at 1 h postexercise. mRNA expression was determined using qRT-PCR. At rest, hVps34 mRNA was elevated in the older subjects (P < 0.05) while there was a tendency for levels of myoD, myogenin, and TSC2 mRNA to be higher than young. The anabolic stimulus (RE+EAA) altered mRNAs associated with mTOR regulation. Notably, REDD2 decreased in both age groups (P < 0.05) but the expression of Rheb mRNA increased only in the young. Finally, cMyc mRNA was elevated (P < 0.05) in both young and old at 6 h post RE+EAA. Furthermore, RE+EAA also increased expression of several mRNAs associated with satellite function in the young (P < 0.05), while expression of these mRNAs did not change in the old. We conclude that several anabolic genes in muscle are more responsive in young men post RE+EAA. Our data provide new insights into the regulation of genes important for transcription and translation in young and old human skeletal muscle post RE+EAA.
 ...
PMID:Expression of growth-related genes in young and older human skeletal muscle following an acute stimulation of protein synthesis. 1878 87

Chronic kidney disease (CKD) impairs muscle protein metabolism leading to muscle atrophy, and exercise can counteract this muscle wasting. Here we evaluated how resistance exercise (muscle overload) and endurance training (treadmill running) affect CKD-induced abnormalities in muscle protein metabolism and progenitor cell function using mouse plantaris muscle. Both exercise models blunted the increase in disease-induced muscle proteolysis and improved phosphorylation of Akt and the forkhead transcription factor FoxO1. Muscle overloading, but not treadmill running, corrected protein synthesis and levels of mediators of protein synthesis such as phosphorylated mTOR and p70S6K in the muscles of mice with CKD. In these mice, muscle overload, but not treadmill, running, increased muscle progenitor cell number and activity as measured by the amounts of MyoD, myogenin, and eMyHC mRNAs. Muscle overload not only increased plantaris weight and reduced muscle proteolysis but also corrected intracellular signals regulating protein and progenitor cell function in mice with CKD. Treadmill running corrects muscle proteolysis but not protein synthesis or progenitor cell function. Our results provide a basis for evaluating different types of exercise on muscle atrophy in patients with chronic kidney disease.
 ...
PMID:Exercise ameliorates chronic kidney disease-induced defects in muscle protein metabolism and progenitor cell function. 1964 84


1 2 3 4 5 Next >>