Muscle and Molecular Biology Unit, Department of Veterinary Basic Sciences, Royal Veterinary College, University of London, London, United Kingdom
Submitted 16 July 2004 ; accepted in final form 4 October 2004
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ABSTRACT |
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differentiation; myocyte enhancer factor
There are two major stages in the differentiation of skeletal muscle cells: the withdrawal from the cell cycle of myoblasts and the subsequent induction of myotube-specific gene expression (4, 8, 20, 30). Once fully differentiated, skeletal muscle myofibers can still undergo changes in phenotype in response to a variety of stimuli, including mechanical stretch (26). Although this process is still poorly understood, recent studies have implicated a number of second messenger signaling pathways and transcription factors involved in the regulation of muscle fiber phenotype. For example, both the myocyte enhancer factor 2 (MEF2) and nuclear factor of activated T cells (NFAT) families of transcription factors have been shown to be involved in the alteration of the fiber phenotype through the Ca2+-dependent phosphatase calcineurin by motor nerve stimulation or work overload (9, 43). Furthermore, these changes can be inhibited by the use of cyclosporine A (CsA), a known inhibitor of calcineurin activity, suggesting the involvement of calcineurin in the regulation of both MEF2 and NFAT mediating phenotypic alteration.
Recent studies have shown that - and
-isoforms of the mitogen-activated protein kinase (MAPK) p38 can promote MEF2 expression during muscle differentiation and that they also are involved in the transcriptional activation of MEF2 proteins through their phosphorylation (10, 44, 47, 49). Two members of the MEF2 family are known to be responsive to p38, namely, MEF2A and MEF2C that bind to the DNA consensus sequence CTA(A/T)4TA(G/A) (6, 49). This sequence is found in the promoter region of numerous muscle-specific genes, especially those related to skeletal muscle fiber specificity (9). Although NFAT has been shown not to be involved in certain specific components of the differentiation process (17), this transcription factor is necessary in combination with MEF2A to allow a change in fiber specificity postdifferentiation (9, 14, 43).
In the present study, we have examined, for the first time, the effect of short-term static stretch on C2C12 myocytes upon NFATc1 and MEF2A phosphorylation states and the second putative messenger signaling pathway involved in this activation.
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MATERIALS AND METHODS |
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Static stretch application.
The medium was renewed with fresh serum on the day before the initiation of experiments. The next day, CsA (Sigma) and SB-203580 (Calbiochem) were added as necessary to achieve final concentrations of 4 and 1 µM, respectively. To allow stretch of the C2C12 cells, we used specific six-well plates containing a silicon membrane coated with collagen. This system was previously used for stretching skeletal muscle cells in vitro (13, 23). A continuous stretch of the silicon basal membrane of a well was produced by placing centrally, under the well, a glass bead of radius 1.6 cm as described previously (unpublished results). To maintain a constant global deformation, we placed a lead weight on top of the plate to maintain pressure on the well to ensure constant, steady deformation of the silicon basal membrane. In that way, the surface stretched can be separated into two areas, denoted S1 and S2 (see Fig. 1). On the basis of the geometry of this system (i.e., symmetry around an axis perpendicular to the base of the well passing through the center of the bead), calculations using trigonometry and differential geometry showed that the deformation applied on S1 was constant and did not depend on the distance between the center and the periphery of the well (as is obvious on the basis of examination of the lateral view of the system, in which S1 is represented by a line with a constant rate). Because the bead produced a parabolic shape, the last result for S1 did not apply to the area S2 at the top of the bead, meaning that the deformation in this region depended on the distance between the center and the circumference of S2. Nonetheless, taking into account the dimensions of the well, we calculated that such a nonhomogeneous local deformation represented only 5% [S2/(S1 + S2) x 100 = 5%] of the total relative increase in the surface area, suggesting a minor contribution to the global stretch. Finally, a calculation showed that the relative increase in the total surface area, e.g., the global deformation, equal to (S1 + S2 S0)/S0, was 89% (where S0 is the surface area of the silicon membrane without stretch).
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Measurement of fluorescence intensity. Fluorescence intensity was measured using dedicated software (EMBL-Zeiss). For each experiment, 70 cells were randomly selected in different fields, with each field containing five to seven cells. The fluorescence intensity of each nucleus was examined on a scale of intensity between 0 (no intensity) and 250 (saturating intensity). Subsequently, the number of nuclei corresponding to a given intensity was plotted as a function of intensity. These data produced Gauss-like curves determining the mean intensity of each experiment.
Western blotting.
Incubations were terminated by washing with ice-cold PBS containing orthovanadate (Na3VO4) at 0.4 mM and whole cell lysates prepared in lysis buffer [63.5 mM Tris·HCl, pH 6.8, 10% glycerol (vol/vol), 2% SDS (wt/vol), 1 mM Na3VO4, 1 mM AEBSF, 50 µg/ml leupeptin, 5% -mercaptoethanol (vol/vol), and 0.02% bromophenol blue (wt/vol)]. The protein content of the cell lysate was measured using the Bradford test (Sigma) and a spectrophotometer (Spectronic Genesys 2; Thermo Electron, Waltham, MA), and equal quantities of protein (3060 µg/lane) were resolved using SDS-PAGE (10 or 7%). The gel was then transferred onto Hybond-P membrane (Amersham, Piscataway, NJ) that was then blocked with nonfat dry milk at 5% (wt/vol) in PBS-Tween (1:1,000 vol/vol). For immunodetection, the following primary antibodies were used at a concentration of 1:1,000 (vol/vol) in PBS-Tween for 1 h: NFATc1, MEF2A, GSK-3
-p(Ser9), Akt1-p(Ser473), GSK-3
, Akt1, p38-p, and p38. The membrane was subsequently washed five times for 10 min each in PBS-Tween. HRP-conjugated antibody was added at a concentration of 1:10,000 (vol/vol) in PBS-Tween for 1 h, and the membrane was washed five times for 10 min each in PBS-Tween before the chemiluminescence reaction was performed using ECL Plus (Amersham). Protein levels were examined using Hyperfilm (Amersham). The measurement of the protein expression levels was performed with an imaging densitometer (GS-690; Bio-Rad, Hercules, CA). To ensure equal loading of the proteins, the blots were stripped and reprobed using either the nonphosphorylated form of the protein studied when necessary or Coomassie blue staining.
Data analysis. Each experiment was repeated six times. All data are expressed as means ± SD. Paired t-test analysis was performed, and significance was accepted at P < 0.05.
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RESULTS |
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Incubation of CsA prevented the stretch-induced changes in phosphorylation of both MEF2A and NFATc1 over the entire time course studied (Fig. 6, A2 and B2). Furthermore, CsA incubation alone (without stretch) did not change the phosphorylation of these proteins (Fig. 6, A1 and B1). Finally, to determine whether CsA impairs stretch-induced p38 phosphorylation, we also measured the level of p38-p when stretch was applied and found no differences between incubation of CsA with or without static stretch (Fig. 7A). These data suggest that under static stretch conditions, both p38 and calcineurin are involved in the changes in phosphorylation states of both NFATc1 and MEF2A. Moreover, a comparison of NFATc1 phosphorylation-dephosphorylation in the presence of SB-203580 when static stretch was applied suggests that p38 is involved in NFATc1 phosphorylation, whereas calcineurin is involved in its dephosphorylation. Interestingly, in the case of MEF2A, a comparison of Figs. 4B and 6B suggests that in response to short-term static stretch, p38 and calcineurin also have opposite effects on MEF2A phosphorylation. However, even if p38 promotes MEF2A phosphorylation in response to short-term static stretch, this kinase is also involved in the dephosphorylation of MEF2A over long-term static stretch (>30 min) in association with calcineurin, because CsA inhibits any change in MEF2A phosphorylation over the entire time course when static stretch is applied. Therefore, it seems that without p38 activation, stretch-induced MEF2A dephosphorylation cannot be sustained, suggesting that p38 is acting in a permissive manner.
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DISCUSSION |
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Role of p38 in stretch-induced NFATc1 and MEF2A phosphorylation.
p38 is a member of the stress-activated kinase family, and p38 - and
-isoforms have been shown to be involved in myogenic differentiation (8, 12, 44, 48). Moreover, p38 isoforms
and
also are involved in the transcriptional regulation of MEF2 proteins via direct phosphorylation (10, 44, 47, 49). In addition, MEF2 and NFAT proteins in association with calcineurin are known to be involved in the regulation of muscle fiber types in adult skeletal muscle (14, 43). Furthermore, because both p38 and MEF2A have been shown to play a role in muscle differentiation, it might be expected that cross talk between these factors could occur during the earlier stages of the differentiation process.
We initially examined the effect of static stretch on the phosphorylation states of the potential modulators of muscle phenotype and/or differentiation MEF2A, MEF2C, and NFATc1. Whereas we observed no changes in MEF2C phosphorylation during the time course studied in response to static stretch (data not shown), a transitory dephosphorylation of NFATc1 was observed during the initial 1-h period. In contrast, the same stretch stimulus triggered no change in MEF2A phosphorylation during the initial 30 min, but this was followed by almost complete dephosphorylation. Different second messenger signaling pathways have been shown to be involved in these phosphorylation processes. Our results demonstrate a decrease in Akt phosphorylation in response to stretch during the time course studied, suggesting that PI3-K activation is not involved (41). In contrast, we found an increase in both p38 and GSK-3 phosphorylation.
To further examine the role of p38, we used SB-203580, a specific downstream inhibitor of activated p38-p (1, 7). Incubation with the drug in the presence of static stretch resulted in sustained NFATc1 dephosphorylation for almost the entire time course studied, as opposed to stretch alone, in which this dephosphorylation was transient. Under the same conditions, the profile of MEF2A phosphorylation-dephosphorylation was the reverse of that seen in response to static stretch alone. Interestingly, we observed that both GSK-3 and Akt phosphorylation were altered with SB-203580 incubation. Therefore, we can presume that cross talk may exist between Akt and p38 on the one hand and GSK-3
and p38 on the other when the stretch is applied.
The mechanism by which a mechanical signal is transduced into intracellular phosphorylation events is at present unclear. However, Aikawa et al. (1) suggested that in cardiac myocytes, mechanical stress is directly sustained by integrins, which in turn activate focal adhesion kinase (FAK), an integrin-associated kinase. It was suggested that phosphorylation of FAK, in turn, leads directly to phosphorylation of p38. Among other putative mechanosensors, such as the involvement of ion channels, this one could explain our observations. However, whether a similar mechanism is involved in the response of C2C12 cells to static stretch remains to be elucidated.
Effects of calcineurin on stretch-induced phosphorylation of NFATc1 and MEF2. The Ca2+-dependent phosphatase calcineurin is known to be involved in the regulation of muscle phenotypes via NFAT and MEF2 activation (9, 14, 43) as well as during differentiation (17, 18, 35). Therefore, using CsA, we decided to investigate how the inhibition of p38 and calcineurin activities would change the profile of NFATc1 and MEF2A phosphorylation-dephosphorylation (28). The addition of CsA in conjunction with passive stretch inhibited change in both MEF2A and NFATc1. Moreover, comparison of our data regarding the effects of SB-203580 and CsA incubation suggests the existence of competition between p38 and calcineurin with regard to MEF2A and NFATc1 phosphorylation states. NFATc1 dephosphorylation occurs via calcineurin, in contrast to p38, which seems to promote its phosphorylation. With regard to MEF2A, calcineurin seems to promote its dephosphorylation during the short exposure to static stretch, whereas p38 tends to promote its phosphorylation. However, during a longer-term, 3-h static stretch, it seems unlikely that calcineurin alone is involved in a biphasic effect on MEF2A phosphorylation, mainly because the Ca2+-dependent calcineurin is a phosphatase. This result suggests that another protein might be involved during long-term stretch that is upregulated (or activated) by SB-203580 administration and sensitive to CsA. That different signaling factors (p38 and calcineurin) are recruited to the differentiation process indicates that both second messengers could be involved in a specific manner in stretch-induced acceleration of skeletal muscle differentiation. Because this process is multifaceted and involves altered gene expression, cell fusion, and growth, it is likely that a number of parallel pathways are involved.
Nuclear translocation of NFATc1 and MEF2.
MEF2A and NFATc1 are transcription factors, and we examined whether they were translocated to the nucleus in response to stretch. After stretching cells for 15 min and 1 h, we stained both NFATc1 and MEF2A with or without drug incubation. At 15 min, we observed no stretch-induced change in nuclear translocation for either factor (data not shown). After a 1-h static stretch, MEF2A, but not NFATc1, nuclear translocation was demonstrated. In addition, both SB-203580 and CsA treatment inhibited MEF2A nuclear translocation. Our observations concerning NFATc1 are in contrast to previous results obtained in cardiac muscle, which showed continuous dephosphorylation of NFATc1 using a dominant negative of p38 to trigger its nuclear translocation and cell hypertrophy in a calcineurin-dependent manner (7). A number of possible explanations concerning the absence of NFATc1 nuclear translocation can be suggested. First, when stretch is applied without drug incubation, NFATc1 is only temporarily dephosphorylated by calcineurin, and this might be insufficient to promote its nuclear import at the myocyte stage compared with fully differentiated myotubes. Second, GSK-3 activity has been shown to promote NFAT nuclear export (5, 42). Therefore, after 1 h of static stretch application, GSK-3
may not be sufficiently deactivated, because it is maximally deactivated at 30 min after the initiation of the stretch stimulus. Third, dephosphorylation of NFATc1 at different sites can occur and might be highly complex with regard to import and export to the nucleus.
Potential relationship between p38 and calcineurin due to static stretch.
Studies of different cell types have shown that p38 activation induces MEF2A phosphorylation and subsequent nuclear translocation, allowing MEF2A/DNA interaction and transcription (10, 27, 43, 4749). However, other studies performed notably on C2C12 myoblasts have shown that calcineurin promotes MEF2A dephosphorylation, which increases its transcriptional activity (27, 43). In the present study, MEF2A phosphorylation seemed to be tightly controlled by both p38 and calcineurin. Although our results have shown MEF2A hypophosphorylation and nuclear location after 1 h of static stretch, this was prevented by SB-203580 incubation, which promoted its phosphorylation and inhibited its nuclear localization. These results suggest that both p38 and calcineurin activation are necessary to trigger and maintain MEF2A nuclear translocation, allowing its hypophosphorylated state to potentially modulate transcription. Interestingly, however, SB-203580 incubation alone seems to promote MEF2A phosphorylation similar to that observed during longer-term stretch (13 h). This suggests that p38 might indirectly antagonize MEF2A hyper-phosphorylation, impairing its nuclear import or participating in its nuclear export. At this stage, the signaling factors responsible for this effect are unknown. However, the recent study of MEF2A phosphorylation by Cox et al. (10) using mass spectroscopy demonstrated that MEF2A is phosphorylated at different sites in response to different kinases. They proposed that among these kinases, GSK-3 activity is probably involved in the phosphorylation of MEF2A on Ser255. It is also noteworthy that studies have shown that GSK-3
activation negatively regulates NFAT nuclear translocation (42) and that, conversely, deactivation of GSK-3
via phosphorylation on Ser9 promotes NFAT nuclear translocation and hypertrophy in both skeletal myotubes and cardiac muscle in vivo (5, 42). Because MEF2A and NFAT are transcription factors involved in expression of contractile proteins and are also implicated in change of phenotype as well as hypertrophy (14, 21), we may expect a common regulation of these proteins, probably involving GSK-3
. This hypothesis is supported by the fact that under static stretch application, our results show cross talk between p38 and GSK-3
, because incubation of SB-203580 can alter increases of GSK-3
phosphorylation on Ser9 (Fig. 5B). It seems, therefore, that both p38 and calcineurin, certainly in association with at least one other signaling protein, play a complex role in MEF2A nuclear translocation in response to a mechanical stimulus. A summarized view containing this hypothesis is shown in Fig. 10.
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Stretch-induced upregulation of neonatal MHC. The transcription factor of MEF2 is known to regulate the expression of MHC isoforms in striated muscle cells (9, 14, 15, 43). Moreover, increase in MEF2 activity leads to MHC expression in rhabdomyosarcoma (34). Therefore, when we applied an overnight static stretch, we observed an increase in the protein level of MHCneo, suggesting an accelerated rate of differentiation of the C2C12 myocytes. Both SB-203580 and CsA prevented this. However, at this stage, we cannot rule out that cofactors are also triggered by static stretch and are sensitive to the inhibitors used. For example, the possible expression of growth factors such as IGF-I as a specific response to overnight passive stretch could be involved in accelerated MHCneo expression. Studies are ongoing to clarify this point. Therefore, expression of MHCneo might not be triggered by MEF2A nuclear translocation alone, because possible involvement of other cellular elements cannot be ruled out.
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CONCLUSIONS |
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More specifically, environmental changes are known to trigger adaptive responses in muscle phenotype via expression of contractile proteins such as MHC isoforms. In the present study, we aimed to define whether static stretch application on myocytes could change the rate of the differentiation process with regard to MHC expression as well as which short-term signaling pathways might be involved. We focused our study on myocytes to determine how MEF2A and NFATc1 are regulated in response to mechanical strain. We showed that the involvement of calcineurin and p38 are crucial, but also complex, in promoting MEF2A nuclear translocation. We also demonstrated that neonatal MHC expression is influenced by static stretch. The rapid activation of signaling pathways in response to a mechanical stimulus suggests that even a short-term stimulus may elicit a signaling cascade that could lead to an acceleration of differentiation. This could lead to an accelerated expression of contractile proteins such as MHC that in turn could accelerate sarcomere formation with concomitant earlier functional contractility within the myotube. During development, muscle fibers are formed in waves, with the majority of secondary fibers forming on a scaffold of earlier-formed primary fibers. Mechanical stimuli elicited by either gradual limb elongation or movement of the embryo in utero may play a crucial role in the rate of development of these fibers. There is also evidence that mechanical stimuli may play an important role in maintaining the differentiated state in the postnatal animal (16). Our laboratory (26) previously showed that stretch induces a slow phenotype in adult muscle, whereas the opposite is the case when stretch is prevented. Recent in vivo and in vitro studies have suggested that mechanical stimuli in adult muscle also induce MEF2 activation in a p38-dependent manner (3). Whether these signaling pathways are crucial to mechanical regulation of postnatal muscle phenotype is at present unclear, however. Therefore, we support the network of evidence that exogenous stimuli such as static stretch contribute to MHC expression even during the early stages of skeletal muscle development, potentially changing the rate of differentiation.
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GRANTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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