ARTICLE |
Correspondence to: Katsuya Kami, Dept. of Health Science, Osaka Univ. of Health and Sport Sciences, Asashirodai 1-1, Kumatori-cho, Sennan-gun, Osaka 590-0496, Japan. E-mail: kami@ouhs.ac.jp
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Summary |
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Although growth factors and cytokines play critical roles in skeletal muscle regeneration, intracellular signaling molecules that are activated by these factors in regenerating muscles have been not elucidated. Several lines of evidence suggest that leukemia inhibitory factor (LIF) is an important cytokine for the proliferation and survival of myoblasts in vitro and acceleration of skeletal muscle regeneration. To elucidate the role of LIF signaling in regenerative responses of skeletal muscles, we examined the spatial and temporal activation patterns of an LIF-associated signaling molecule, the signal transducer and activator transcription 3 (STAT3) proteins in regenerating rat skeletal muscles induced by crush injury. At the early stage of regeneration, activated STAT3 proteins were first detected in the nuclei of activated satellite cells and then continued to be activated in proliferating myoblasts expressing both PCNA and MyoD proteins. When muscle regeneration progressed, STAT3 signaling was no longer activated in differentiated myoblasts and myotubes. In addition, activation of STAT3 was also detected in myonuclei within intact sarcolemmas of surviving myofibers that did not show signs of necrosis. These findings suggest that activation of STAT3 signaling is an important molecular event that induces the successful regeneration of injured skeletal muscles. (J Histochem Cytochem 50:15791589, 2002)
Key Words: STAT3, MyoD, PCNA, satellite cell, muscle regeneration
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Introduction |
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ADULT SKELETAL MUSCLES are able to vigorously regenerate after damage, and muscle precursor cells (mpcs), which are normally present as satellite cells, play a critical role in muscle regeneration. In normal adult muscles, satellite cells are maintained in a quiescent state (quiescent satellite cell), but when skeletal muscles are damaged, activated satellite cells, widely called myoblasts, start to vigorously proliferate. After proliferation, differentiated myoblasts express muscle-specific genes, such as myosin, muscle creatine kinase, and acetylcholine receptors, and fuse to form multinucleated myotubes (
The sequential but distinctive events of mpcs in regenerating muscles are regulated by growth factors and cytokines, such as the hepatocyte growth factor (HGF), the fibroblast growth factors (FGFs), the platelet-derived growth factor (PDGF), the insulin-like growth factors (IGFs), and the leukemia inhibitory factor (LIF) (
The action of LIF on skeletal muscle regeneration is mediated by a functional LIF receptor composed of two signal-transducing proteins, LIF receptor-ß (LIFR) and gp130. It has been reported that rapid upregulation of these two receptor mRNAs after muscle injury was detected in myonuclei and/or nuclei of mpcs in injured muscles but that these signals disappeared in newly formed myotubes (
We analyzed the activation of STAT3 signaling in the regeneration of skeletal muscles induced by crush injury, identifying mpcs and distinct regenerative stages of mpcs (i.e., activation, proliferation, and differentiation). In this study, satellite cells were identified by c-Met, dystrophin, and laminin immunolabeling, and nuclei expressing both proliferating cell nuclear antigen (PCNA) and MyoD proteins were identified as nuclei of proliferating myoblasts. Expressions of the cyclin-dependent kinase inhibitor p21, myogenin, and AchR in myoblasts determined that these myoblasts were in the post-mitotic stage. The present study shows that rapid phosphorylation and nuclear translocation of STAT3 proteins are exclusively induced in the activated satellite cells, proliferating myoblasts, and surviving myofibers during skeletal muscle regeneration. These results provided a molecular basis for further understanding of the muscle regeneration mechanism.
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Materials and Methods |
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Muscle Crush Injury and Tissue Preparation
Adult Wistar rats (200250 g) were used in this study. Muscle crush injury was achieved without a skin incision as described previously (
Immunostaining
Primary antibodies used in this study were as follows: a rabbit polyclonal anti-laminin (1:3000; Sigma, St Louis, MO), a rabbit polyclonal anti-phospho STAT3 (Tyr705) (P-STAT3) (1:100; Cell Signaling, Beverly, MA), a mouse monoclonal anti-MyoD (1:50; DAKO, Carpinteria, CA), a mouse monoclonal anti-dystrophin (1:100; Sigma), a mouse monoclonal anti-desmin (1:100; Zymed, So. San Francisco, CA), a mouse monoclonal anti-cyclin-dependent kinase inhibitor p21 (1:50; BD PharMingen, San Diego, CA), a mouse monoclonal anti-c-met (1:50; Santa Cruz Biotech., Santa Cruz, CA), and a mouse monoclonal anti-PCNA (1:50; DAKO).
Five-µm or 12-µm frozen cross-sections were mounted on 3-amino-propylethoxysilane-coated slides and fixed with 4% paraformaldehyde in a 0.1 M phosphate buffer (pH 7.4) for 15 min. The sections were then washed in 0.1 M PBS and incubated with 0.1 M PBS containing 10% normal serum and 0.3% Triton X-100 at room temperature (RT) to block nonspecific staining. For triple-immunofluorescence staining, the sections were incubated simultaneously with the primary antibodies diluted with 0.1 M PBS containing 5% normal donkey serum, 0.3% Triton X-100 from 16 hr to 48 hours at 4C. The sections were washed in 0.1 M PBS and incubated with the secondary antibodies diluted with 0.1 M PBS containing 5% normal donkey serum, 0.1% Triton X-100 overnight at 4C. Fluorescein-conjugated donkey anti-mouse IgG was used for the mouse monoclonal primary antibodies and rhodamine-conjugated donkey anti-rabbit IgG was used for the rabbit polyclonal antibodies (Chemicon; Temecula, CA). The sections were then washed in 0.1 M PBS, and mounted in Vectashield mounting medium with DAPI (Vector Labs; Burlingame, CA) to visualize the nuclei. Immunofluorescence-stained sections were viewed on an Olympus microscope with epifluorescence using a x20 or x40 objective.
For immunohistochemical staining, the sections were incubated with the primary antibody diluted with 0.1 M PBS containing 5% normal goat or horse serum, 0.3% Triton X-100 from 16 hr to 48 hr at 4C. The sections were washed in 0.1 M PBS and incubated with the biotin-conjugated secondary antibodies diluted with 0.1 M PBS containing 5% normal goat or horse serum, 0.1% Triton X-100 at RT. Biotin-conjugated horse anti-mouse IgG was used for the mouse monoclonal primary antibodies (Vector Labs) and biotin-conjugated goat anti-rabbit IgG was used for the rabbit polyclonal antibodies (Chemicon). The sections were then washed in 0.1 M PBS, and incubated with a Vectastain Elite ABC kit (Vector) and diaminobenzidine (DAB). Immunostained sections were stained with hematoxylin to visualize the nuclei.
Probes for In Situ Hybridization
The oligonucleotide probe for acetylcholine receptor- (AchR) was complementary to nucleotides 12161263 of the published rat AchR sequences (
In Situ Hybridization
Frozen cross-sections of gastrocnemius muscle 12 µm thick were thawed on 3-amino-propylethoxysilane-coated slides, then hybridized with radiolabeled probes as follows. Sections were fixed with 4% paraformaldehyde in a 0.1 M phosphate buffer (pH 7.4) for 15 min, then rinsed in 2 x SSC (0.3 M NaCl, 30 mM Na citrate). The sections were incubated with 1 µg/ml proteinase K (Sigma) at 37C for 5 min. After two rinses in 2 x SSC, they were dehydrated in 70%, 80%, 90%, 95%, and 100% ethanol, then air-dried. The sections were incubated with a hybridization buffer [50% formamide, 4 x SSC, 0.12 M phosphate buffer, pH 7.4, 1 x Denhardt's solution, 0.2% SDS, 0.25 mg/ml tRNA, 10% dextran sulfate, 100 mM dithiothreitol (DTT)] containing the radiolabeled oligonucleotide probes at 37C for 16 hr. After hybridization, the sections were washed with three changes of 1 x SSC at 55C for 20 min each, followed by dehydration in 80%, 90%, 95%, and 100% ethanol, and then air-dried. To visualize the signals for the specific mRNAs, the sections were dipped in Ilford K15 autoradiography emulsion diluted 2:3 with distilled water at 45C. After exposure at 4C for 4 weeks, they were developed in Kodak D19 for 4 min at 20C and then fixed in 24% sodium thiosulfate solution for 5 min. Lastly, the sections were stained with hematoxylin and eosin.
To ascertain the specificity of the nucleotide sequences designed as probes for AchR and myogenin mRNAs, we observed hybridization signals as follows. An AchR oligonucleotide probe revealed distinct signals in the neuromuscular junctions of the intact myofibers and myonuclei of denervated myofibers. The myogenin oligonucleotide probe has been characterized previously (
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Results |
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Myonuclei Express Activated STAT3 Proteins
To investigate whether the STAT3 signaling pathway was activated in regenerating muscles after muscle crush injury, we performed immunohistochemical staining with a specific antibody for the Tyr705-phosphorylated form of STAT3 protein (P-STAT3). STAT3 proteins were detected as inactivated forms in various cells, including skeletal muscles and motor neurons (
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Activation of STAT3 Signaling in Activated Satellite Cells
To investigate if activation of STAT3 signaling is induced in satellite cells in regenerating muscles, satellite cells were identified using two strategies. Previous studies showed that c-Met, a receptor for hepatocyte growth factor (HGF), is expressed in both quiescent and activated satellite cells (
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Satellite cells are located between the sarcolemma and basement membrane of myofibers. On the basis of this feature, we identified satellite cells by triple and double immunostaining on 5-µm serial sections. Mammalian satellite cell dimensions are approximately 25 x 4 x 5 µm, and lengths of the rat satellite cell nucleus average 912 µm (
Activation of STAT3 Signaling in Proliferating Myoblasts
MyoD plays critical roles in development and regeneration of skeletal muscles, and rapid upregulation of MyoD mRNA and protein after muscle injury is detected in nuclei of all myogenic cells and myonuclei (
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To identify proliferating myoblasts in regenerating muscles, we performed triple and double immunostaining on adjacent serial sections prepared at a thickness of 5 µm as mentioned above. It has been known that proliferating cell nuclear antigen (PCNA) is an auxiliary protein of DNA polymerase , whose level correlates with DNA synthesis during the cell cycle, being maximal during the S-phase (
Activation of STAT3 Signaling Disappears in Differentiated Myoblasts and Myotubes
Myoblasts that stop proliferating are induced into the differentiation stage. Myotube formations in regenerating muscles progress within basement membranes as a scaffold for myoblast differentiation and then fuse, so that the myoblasts are frequently detected as a ring-like structure (
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We assayed to ascertain whether activation of STAT3 signaling was also induced in differentiated myoblasts by immunostaining with MyoD and P-STAT3 antibodies. At day 3 after injury, MyoD-positive myoblasts were observed as a ring-like structure inside the remaining basement membranes (Fig 5A5C), and analysis using serial sections showed that P-STAT3 could not be detected in these myoblasts (Fig 5D and Fig 5E). Furthermore, at day 5 after injury, many myo-tubes that had centrally located p21- and MyoD-positive nuclei in their cytoplasm were detected, but activation of STAT3 signaling was not observed in myotubes (data not shown). The expression patterns for c-Met, MyoD, PCNA, p21, and P-STAT3 proteins in regenerating muscles are summarized in Table 1.
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Discussion |
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Muscle regeneration progresses through sequential events consisting of activation, proliferation, differentiation, and survival of mpcs. Therefore, to determine the relationship between activated signaling molecules and the stages of mpcs, it is important to understand the molecular mechanisms of muscle regeneration. It is well known that the entire process of muscle regeneration is regulated by growth factors and cytokines (
Possible Factors that Activate STAT3 Signaling
As mentioned above, rapid phosphorylation and translocation into nuclei of STAT3 proteins were induced at a considerably early time point (3 hr to day 1 after injury) after muscle injury. These results imply that an upstream factor(s) and their specific receptors connected to STAT3 signaling must also be induced in injured muscles at this time point. STAT3 is activated preferentially by the members of the IL-6 family of cytokines ( (IL-6R), a ligand-binding receptor in a functional IL-6 receptor complex, was exclusively expressed in interstitial mononuclear cells but not in myofibers or mpcs during muscle regeneration (
LIF also contributes to the formation of larger myotubes in vitro (
Possible Target Genes and Functions of Activated STAT3 Protein
Although phosphorylated STAT3 is rapidly translocated into nuclei to function as a transcription factor, the genes that are directly transactivated by STAT3 in skeletal muscles are not yet elucidated. In other cells, potential STAT3 target genes have been shown to include Bcl-2 and Bcl-xL, which act as anti-apoptosis factors (
In an attempt to investigate regulation of cell death, neonatal muscles of Bcl-2-null mice revealed a reduced myofiber number compared with wild-type mice (
Other potential STAT3 target genes are c-fos, junB, and cyclin D1 (
In summary, we have shown that activation of STAT3 signaling was exclusively induced in the activated satellite cells, proliferating myoblasts, and surviving myofibers in regenerating muscles, and LIF may be one of the strong upstream factors to activate this molecule. Protection of activated satellite cells, proliferating myoblasts and surviving myofibers from apoptotic cell death and inhibition of myoblast differentiation at the early regenerative stage are essential for complete muscle regeneration. Therefore, we propose that activated STAT3 may be an important signaling molecule that mediates these functions at the early stage of skeletal muscle regeneration.
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Acknowledgments |
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Supported in part by a grant-in-aid (13670030) for Scientific Research from the Ministry of Education, Science, and Culture of Japan.
Received for publication November 5, 2001; accepted June 26, 2002.
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Literature Cited |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Allbrook D (1981) Skeletal muscle regeneration. Muscle Nerve 4:234-245[Medline]
Anderson JE (2000) A role for nitric oxide in muscle repairs: nitric oxide-mediated activation of muscle satellite cells. Mol Biol Cell 11:1859-1874
Austin L, Bower J, Kurek J, Vakakis N (1992) Effects of leukaemia inhibitory factor and other cytokines on murine and human myoblast proliferation. J Neurol Sci 112:185-191[Medline]
Barnard W, Bower J, Brown MA, Murphy M, Austin L (1994) Leukemia inhibitory factor (LIF) infusion stimulates skeletal muscle regeneration after injury: injured muscle expresses LIF mRNA. J Neurol Sci 123:108-113[Medline]
Baserga R (1991) Growth regulation of the PCNA gene. J Cell Sci 98:433-436[Medline]
Bottaro DP, Rubin JS, Faletto DL, Chan AM, Kmiecik TE, Vande Woude GF, Aaronson SA (1991) Identification of the hepatocyte growth factor receptor as the c-met protooncogene product. Science 251:802-804[Medline]
Bravo R, Frank R, Blundell PA, MacdonaldBravo H (1987) Cyclin/PCNA is the auxiliary protein of DNA polymerase-d. Nature 326:515-517[Medline]
Bromberg JF (2001) Activation of STAT proteins and growth control. BioEssays 23:161-169[Medline]
Chambers RL, McDermott JC (1996) Molecular basis for skeletal muscle regeneration. Can J Appl Physiol 21:155-184[Medline]
Coffer P, Lutticken C, van Puijenbroek A, Klopde Jonge M, Horn F, Kruijer W (1995) Transcriptional regulation of the junB promoter: analysis of STAT-mediated signal transduction. Oncogene 10:985-994[Medline]
Cooper RN, Tajbakhsh S, Mouly V, Cossu G, Buckingham M, ButlerBrowne GS (1999) In vivo satellite cell activation via Myf5 and MyoD in regenerating mouse skeletal muscle. J Cell Sci 112:2895-2901
Dominov JA, Dunn JJ, Miller JB (1998) Bcl-2 expression identifies an early stage of myogenesis and promotes clonal expansion of muscle cells. J Cell Biol 142:537-544
Dominov JA, HoulihanKawamoto CA, Swap CJ, Miller JB (2001) Pro- and anti-apoptotic members of the Bcl-2 family in skeletal muscle: a distinct role for Bcl-2 in later stages of myogenesis. Dev Dyn 220:18-26[Medline]
Ebisui C, Tsujinaka T, Morimoto T, Kan K, Iijima S, Yano M, Kominami E et al. (1995) Interleukin-6 induces proteolysis by activating intracellular protease (cathepsins B and L, proteasome) in C2C12 myotubes. Clin Sci 89:431-439[Medline]
Florini JR, Ewton DZ, Magri KA (1991) Hormones, growth factors, and myogenic differentiation. Annu Rev Physiol 53:201-216[Medline]
Fuchtbauer EM, Westphal H (1992) MyoD and myogenin are coexpressed in regenerating skeletal muscle of the mouse. Dev Dyn 193:34-39[Medline]
Fukada T, Hibi M, Yamanaka Y, TakahashiTezuka M, Fujitani Y, Yamaguchi T, Nakajima K et al. (1996) Two signals are necessary for cell proliferation induced by a cytokine receptor gp130: involvement of STAT3 in anti-apoptosis. Immunity 5:449-460[Medline]
Goodman MN (1994) Interleukin-6 induces skeletal muscle protein breakdown in rats. Proc Soc Exp Biol Med 205:182-185[Abstract]
Grounds MD (1999) Muscle regeneration: molecular aspects and therapeutic implications. Curr Opin Neurol 12:535-543[Medline]
Grounds MD, Garrett KL, Wright WE, Beillharz MW (1992) Identification of skeletal muscle precursor cells in vivo by use of MyoD1 and myogenin probes. Cell Tissue Res 267:99-104[Medline]
Grounds MD, YablonkaReuveni Z (1993) Molecular and cellular biology of muscle regeneration. In Partridge T, ed. Molecular and Cell Biology of Muscular Dystrophy. London, Chapman & Hall, 210-256
Halevy O, Novitch BG, Spicer DB, Skapek SX, Rhee J, Hannon GJ, Beach D et al. (1995) Correlation of terminal cell cycle arrest of skeletal muscle with induction of p21 by MyoD. Science 267:1018-1021[Medline]
Hass CA, Hofmann H-D, Kirsch M (1999) Expression of CNTF/LIF-receptor components and activation of STAT3 signaling in axotomized facial motoneurons: evidence for a sequential postlesional function of the cytokines. J Neurobiol 41:559-571[Medline]
Hurme T, Kalimo H (1991) Activation of myogenic precursor cells after muscle injury. Med Sci Sports Exerc 24:197-205
Jenab S, Morris PL (1996) Differential activation of signal transducer and activator of transcription (STAT)-3 and STAT-1 transcription factors and c-fos messenger ribonucleic acid by interleukin-6 and interferon-gamma in Sertoli cells. Endocrinology 137:4738-4743[Abstract]
Kami K, Kashiba H, Masuhara M, Kawai Y, Noguchi K, Senba E (1993) Changes of vinculin and extracellular matrix components following blunt trauma to rat skeletal muscle. Med Sci Sports Exerc 25:832-840[Medline]
Kami K, Morikawa Y, Kawai Y, Senba E (1999) LIF, GDNF and their receptor expressions following muscle crush injury. Muscle Nerve 22:1576-1586[Medline]
Kami K, Morikawa Y, Sekimoto M, Senba E (2000) Gene expression of receptors for IL-6, LIF and CNTF in regenerating skeletal muscles. J Histochem Cytochem 48:1203-1213
Kami K, Noguchi K, Senba E (1995) Localization of myogenin, c-fos, c-jun and muscle-specific gene mRNAs in regenerating rat skeletal muscle. Cell Tissue Res 280:11-19[Medline]
Kami K, Senba E (1998) Localization of leukemia inhibitory factor and interleukin-6 messenger ribonucleic acids in regenerating rat skeletal muscle. Muscle Nerve 21:819-822[Medline]
Koishi K, Zhang M, McLennan IS, Harris J (1995) MyoD protein accumulates in satellite cells and is neurally regulated in regenerating myotubes and skeletal muscle fibers. Dev Dyn 202:244-254[Medline]
Kurek JB, Bower J, Romanella M, Austin L (1996a) Leukemia inhibitory factor treatment stimulates muscle regeneration in the mdx mouse. Neurosci Lett 212:167-170[Medline]
Kurek JB, Bower JJ, Romanella M, Koentgen F, Murphy M, Austin L (1997) The role of leukemia inhibitory factor in skeletal muscle regeneration. Muscle Nerve 20:815-822[Medline]
Kurek JB, Nouri S, Kannourakis G, Murphy M, Austin L (1996b) Leukemia inhibitory factor and interleukin-6 are produced by diseased and regenerating skeletal muscle. Muscle Nerve 19:1291-1310[Medline]
Lassar AB, Thayer MJ, Overell RW, Weintraub H (1989) Transformation by activated ras or fos prevents myogenesis by inhibiting expression of MyoD1. Cell 58:659-667[Medline]
Li L, Chambard J-C, Karin M, Olson EN (1992) Fos and Jun repress transacriptional activation by myogenin and MyoD: the amino-terminus of Jun can mediate repression. Genes Dev 6:676-689[Abstract]
Liu S, Spinner DS, Schmidt MM, Danielsson JA, Wang S, Schmidt J (2000) Interaction of MyoD family proteins with enhancers of acetylcholine receptor subunit genes in vivo. J Biol Chem 275:41364-41368
Megeney LM, Perry RLS, Lecouter JE, Rundnicki MA (1996) bFGF and LIF signaling activates STAT3 in proliferating myoblasts. Dev Genet 19:139-145[Medline]
Oh H, Fujio Y, Kunishita K, Hirota H, Matsui H, Kishimoto T, YamauchiTakihara K (1998) Activation of phosphatidylinositol 3-kinase through glycoprotein 130 induces protein kinase B and p70 S6 kinase phosphorylation in cardiac myocytes. J Biol Chem 273:703-710
Olive M, Ferrer I (1999) Bcl-2 and Bax protein expression in human myopathies. J Neurol Sci 15:76-81
Rahm M, Jin P, Sumegi J, Sejersen T (1989) Elevated c-fos expression inhibits differentiation of L6 rat myoblasts. J Cell Physiol 139:237-244[Medline]
Rao SS, Chu C, Kohtz DS (1994) Ectopic expression of cyclin D1 prevents activation of gene transcription by myogenic basic helix-loop-helix regulators. Mol Cell Biol 14:5259-5267[Abstract]
Rommel C, Bodine SC, Clarke BA, Rossman R, Nunez L, Stitt TN, Yancopoulos GD et al. (2001) Mediation of IGF-1-induced skeletal myotube hypertrophy by PI(3)K/Akt/mTOR and PI(3)K/Akt/GSK3 pathways. Nature Cell Biol 11:1009-1013
Schultz E, McCormick KM (1994) Skeletal muscle satellite cells. Rev Physiol Biochem Pharmacol 123:213-257[Medline]
Schwaiger F-W, Hager G, Schmitt AB, Horvat A, Hager G, Streif R, Spitzer C et al. (1999) Peripheral but not central axotomy induces changes in Janus kinase (JAK) and signal transducers and activators of transcription (STAT). Eur J Neurosci 12:1165-1176
Skapek S, Rhee J, Spicer DB, Lassar AB (1995) Inhibition of myogenic differentiation in proliferating myoblasts by cyclin D1-dependent kinases. Science 267:1022-1024[Medline]
Taga T (1996) gp130, a shared signal transducing receptor component for hematopoietic and neuropoietic cytokines. J Neurochem 67:1-10[Medline]
Takeda K, Akira S (2000) STAT family of transcription factors in cytokine-mediated biological responses. Cytokine Growth Factor Rev 11:199-207[Medline]
Tatsumi R, Anderson JE, Nevoret CJ, Halevy O, Allen RE (1998) HGF/SF is present in normal adult skeletal muscle and is capable of activating satellite cells. Dev Biol 194:114-128[Medline]
Vakakis N, Bower J, Austin L (1995) In vitro myoblast to myotube transformations in the presence of leukemia inhibitor factor. Neurochem Int 27:29-35
Walsh K (1997) Coordinate regulation of cell cycle and apoptosis during myogenesis. Prog Cell Cycle Res 3:53-58[Medline]
Watkins SC, Cullen MJ (1988) A quantitative study of myonuclear and satellite cell nuclear size in Duchenne's muscular dystrophy, polymyositis and normal human skeletal muscle. Anat Rec 222:6-11[Medline]
White JD, Davies M, Grounds MD (2001) Leukemia inhibitory factor increases myoblast replication and survival and affects extracellular matrix production: combined in vivo and in vitro studies in post-natal skeletal muscle. Cell Tissue Res 306:129-141[Medline]
White JD, Scaffidi A, Davis M, McGeachie J, Rundnicki MA, Grounds MD (2000) Myotube formation is delayed but not prevented in MyoD-deficient skeletal muscle: studies in regenerating whole muscle grafts of adult mice. J Histochem Cytochem 48:1531-1543
Witzemann V, Stein E, Barg B, Konno T, Koenen M, Kues W, Criado M et al. (1990) Primary structure and functional expression of the -, ß-,
-,
, and
-subunits of the acetylcholine receptor from rat muscle. Eur J Biochm 194:437-448
Wright WE, Sassoon DA, Lin VK (1989) Myogenin, a factor regulating myogenesis, has a domain homologous to MyoD. Cell 56:607-617[Medline]
YablonkaReuveni Z (1995) Developmental and postnatal regulation of adult myoblasts. Microsc Res Tech 30:366-380[Medline]
YablonkaReuveni Z, Rivera AJ (1997) Proliferative dynamics and the role of FGF2 during myogenesis of rat satellite cells on isolated fibers. Bas Appl Myol 7:189-202
Zong CS, Chan J, Levy DE, Horvath C, Sadowski HB, Wang L-H (2000) Mechanism of STAT3 activation by insulin-like growth factor I receptor. J Biol Chem 275:15099-15105