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MUSCLE CELL BIOLOGY AND CELL MOTILITY
is required for efficient skeletal muscle regenerationDepartment of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois
Submitted 29 November 2007 ; accepted in final form 14 March 2008
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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is produced endogenously following skeletal muscle injury and promotes efficient healing. We show that IFN- is expressed at both mRNA and protein levels in skeletal muscle following injury, and that the time course of IFN- expression correlated with the accumulation of macrophages, T-cells, and natural killer cells, as well as myoblasts, in damaged muscle. Cells of each type were isolated from injured muscle, and IFN- expression was detected in each cell type. We also demonstrate that administration of an IFN- receptor blocking antibody to wild-type mice impaired induction of interferon response factor-1, reduced cell proliferation, and decreased formation of regenerating fibers. IFN- null mice showed similarly impaired muscle healing associated with impaired macrophage function and development of fibrosis. In vitro studies demonstrated that IFN- and its receptor are expressed in the C2C12 muscle cell line, and that the IFN- receptor blocking antibody reduced proliferation and fusion of these muscle cells. In summary, our results indicate that IFN- promotes muscle healing, in part, by stimulating formation of new muscle fibers. cytokine; inflammation; macrophage; tissue repair
hours-7 days postinjury) involves accumulation of neutrophils, macrophages, and lymphocytes in injured muscle. The regeneration phase (2–7 days) involves the activation and proliferation of quiescent muscle precursor cells called satellite cells, which migrate and fuse to replace damaged fibers. The remodeling phase (5–30 days) involves the growth of newly formed fibers and remodeling of damaged fibers and extracellular matrix. In the present study, we focus on the inflammatory process; inflammatory cells play integral roles in tissue healing, through phagocytosis of tissue debris, and production of cytokines and other factors (8, 21, 36, 38). Unfortunately, the precise roles of these inflammatory cells and cytokines in muscle healing remain largely undefined.
Interferon (IFN)- is an inflammatory cytokine that was first identified as an antiviral factor (41). A primary function of IFN- is to activate macrophages through the classical pathway, which promotes pathogen killing (9). Since those initial findings, IFN- has been recognized as a pleiotropic cytokine that regulates different immune responses and influences many physiological processes. IFN- is thought to be produced primarily by activated T lymphocytes and natural killer (NK) cells, although other cell types may contribute to IFN- production (26, 30). IFN- binds to a specific extracellular membrane receptor and can induce signaling through the janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway, among others (4, 9, 28). During tissue repair, IFN- is thought to be an antifibrotic factor and can reduce synthesis of extracellular matrix by disrupting signaling by the profibrotic cytokine transforming growth factor-β (TGF-β; 19, 40).
IFN- has been found to influence skeletal muscle homeostasis and repair. A transgenic mouse that constitutively overexpresses IFN- at the neuromuscular junction demonstrated an age-dependent necrotizing myopathy (31). On the other hand, transient administration of exogenous IFN- appears to improve healing of skeletal muscle and limit fibrosis (12). Exogenous IFN- appears to have a direct effect on muscle cells in culture, increasing expression of major histocompatability complex (MHC) molecules, intracellular adhesion molecule-1 (ICAM-1), and monocyte chemotactic protein-1 (MCP-1), among others (20, 22, 24, 29, 34). Exogenous IFN- has also been reported to influence proliferation and differentiation of cultured myoblasts derived from human, chicken, and rat muscle (11, 15, 17, 39). However, the role of endogenous IFN- in skeletal muscle repair has not yet been determined.
The hypotheses of this study were that expression of IFN- is upregulated in skeletal muscle following injury and that such endogenously produced IFN- is required for efficient muscle regeneration. To test these hypotheses, we measured IFN- at the mRNA and protein levels following muscle injury and in a muscle cell line. We also measured muscle regeneration following administration of an IFN- receptor blocking antibody to wild-type mice and compared muscle regeneration in wild-type mice and mice deficient in IFN-. Finally, we tested whether the IFN- receptor blocking antibody reduces myoblast proliferation and/or fusion in vitro.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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null mice were obtained from Jackson Laboratories and bred in our animal facility. Mice were housed in a specific pathogen-free environment at a constant temperature and a 12:12 h light-dark cycle. Experiments were performed on 10- to 14 wk-old mice; experimental groups are presented in Table 1. All experimental procedures were approved by the Animal Care Committee at the University of Illinois at Chicago.
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IFN- receptor blocking antibody.
Wild-type mice were treated with either IFN- receptor blocking antibody (ATCC, clone GR-20) or control rat IgG (Southern Biotech) to determine whether blocking IFN- action impairs muscle regeneration. Mice were injected intraperitoneally with 200 µg antibody immediately after injury and daily thereafter for 5 days. This protocol was based on a previous study in which IFN- action was blocked in mice (10). No adverse health effects were observed. One hour before euthanasia, mice were injected with bromodeoxyuridine (BrdU; 30 mg/kg) to allow for assessment of cell proliferation.
Muscle morphology.
Cryosections were cut from the midbelly of each EDL muscle (10 µm thickness) and stained with hematoxylin and eosin for morphological analysis or Masson's trichrome for collagen deposition or processed for inflammatory cell analysis via immunohistochemistry. Morphological analysis was performed using five images obtained using a x40 objective for each muscle section covering 20–25% of the total section and considered to be representative of the entire section (Labphot-2, Nikon; and SPOT software, Diagnostic Instruments). For each field, fibers were classified as normal, damaged, or regenerating as described (18). Regenerating fibers were identified as those containing centrally located nuclei without evidence of damage. The number and area of each type of fiber were recorded. Damaged area was then estimated in each muscle section by subtracting the summed area of normal and regenerating fibers from the total area of each field.
Inflammatory cells. Inflammatory cell accumulation was measured in muscle cross sections using immunohistochemical methods as previously described (18). Sections were incubated for 2 h with primary antibodies (1:100 dilution) for neutrophils (Ly6G; BD Pharmingen), macrophages (F4/80; Serotec), T-cells (CD4; Serotec), or NK cells (CD49b; BD Pharmingen) followed by incubation with biotinylated mouse adsorbed anti-rat IgG (Vector Laboratories). All sections were then developed using Vector Laboratories AEC kit. Two images were captured per section using a x20 objective, and images were analyzed using image analysis software (Scion). For this analysis, the number of pixels staining above threshold intensity were counted and normalized to the total number of pixels. Threshold intensity was set such that only pixels with clearly stained cells were counted.
Cell isolation.
Cells were isolated from TA muscles harvested 5 days after injury from wild-type or IFN- null mice using a protocol modified from the literature (2). Briefly, muscles were dissected, minced, and then digested with 0.1% pronase (Calbiochem). After trituration to dissociate from fiber fragments, the suspension was filtered through 70-µm mesh, the filtrate was centrifuged, and cells were resuspended and counted. Macrophages, T-cells, and NK cells were isolated using microbeads conjugated to a Mac-1, CD4, and CD49b antibodies, respectively, and a magnetic column (Miltenyi Biotec).
Cell culture.
Primary satellite cell cultures were derived from hindlimb muscles of neonatal mice. Briefly, cells were isolated from neonatal muscles using the procedure described in Cell isolation for injured muscle. A preplating technique was used to separate fibroblasts from satellite cells. After a 1-h preplating step, nonadherent cells (primarily satellite cells) were transferred to another dish and grown in selective proliferation medium (Ham's F10, 20% fetal bovine serum, 5 ng/ml bFGF, and 1% penicillin-streptomycin) on entactin-collagen-laminin (ECL; Upstate Biotechnology)-coated dishes in a humidified 5% CO2 atmosphere at 37°C until 70% confluent. Immunofluorescence analysis demonstrated that greater than 90% of myoblasts were positive for MyoD.
C2C12 myoblasts (ATCC), a cell line derived from mouse skeletal muscle satellite cells, were plated at 1 x 105 cells/well in six-well plates in growth medium–Dulbecco's modified Eagles medium (DMEM) supplemented with 10% fetal bovine serum and 1% penicillin-streptomycin (GIBCO) at 37°C and 5% CO2. Cells were grown on coverslips coated with ECL (Millipore) for analysis of proliferation or fusion. For proliferation experiments, after cells were allowed to adhere to coverslips overnight, cells were treated with 10 µg/ml of rat anti-mouse IFN- receptor blocking antibody or control rat IgG for 24 h. One hour before cell harvest, cells were incubated with 100 µM BrdU, and cells were either trypsinized and counted or processed for analysis of BrdU incorporation. For fusion experiments, cells were grown on coverslips to 70% confluence, and then the medium was changed to differentiation medium (DMEM + 2% horse serum). Cells were treated with 10 µg/ml of rat anti-mouse IFN- receptor blocking antibody or control rat IgG for 4 days, and fusion was assessed by determining the percentage of nuclei that were found in myotubes.
Cell proliferation. Cell proliferation and myoblast accumulation was assessed in muscle cross sections. Cell proliferation was also measured in cultured C2C12 cells grown on coverslips. For cell proliferation, samples were fixed in cold acetone, washed in PBS, and incubated in 2 N HCl. Samples were neutralized with basic PBS (pH = 8.5) and then washed with neutral PBS (pH = 7.6). This was followed by incubation in 0.1% IGEPAL and then blocking buffer. Proliferating cells were labeled with a BrdU antibody for 1 h (1:10 Roche Diagnostics). For myoblast accumulation, sections were fixed in cold acetone, washed, blocked, and incubated with a MyoD antibody overnight (1:20, Santa Cruz Biotechnologies). Afterward, samples were washed with PBS and subsequently incubated with FITC anti-mouse secondary antibody (Jackson ImmunoResearch). For muscle sections, the number of positively labeled cells was counted in three fields observed at x20 for two sections per muscle and normalized to the volume of muscle sampled. For C2C12 cells, the number of positively labeled cells was counted in four fields observed at x20 and normalized to the total number of cells present.
RT-PCR. Total RNA was isolated from injured muscle tissue, cells were isolated from injured muscle and cultured C2C12 muscle cells using the RNeasy kit (Qiagen) according to the manufacturer's instructions. RNA quantity was determined by UV absorption at 260 nm, and quality was verified by the 260-to-280 nm ratio and formaldehyde-agarose gel electrophoresis. RNA (2 µg) was reverse transcribed using the Thermoscript RT-PCR kit (Invitrogen, Carlsbad, CA), and PCR was performed with the primers and cycling conditions in Table 2. Conditions were optimized to ensure that each target was within its linear range.
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(1:500, BD Biosciences) or interferon response factor-1 (IRF-1, 1:300, Santa Cruz Biotechnologies), washed, and then incubated with secondary antibody conjugated to horseradish peroxidase (Pierce). After another wash, protein bands were detected using enhanced chemiluminescence (Amersham), and band densities were determined by image analysis (Bio-Rad FluorS).
Statistical analysis.
Values are reported as means ± SE. Measures of IFN- expression and inflammatory cell accumulation were compared between time points using one-way ANOVA. Measures of muscle regeneration were compared between wild-type and IFN- null mice and different time points using two-way ANOVA. The Student-Newman-Keuls test was used for post hoc analysis. Measures of muscle regeneration and in vitro myoblast proliferation and fusion were compared between control antibody versus IFN--blocking antibody-treated conditions using t-tests. The 0.05 level was taken to indicate statistical significance.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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and IFN- receptor expression.
To determine whether IFN- is expressed following skeletal muscle injury, we used RT-PCR and Western blot analysis to assess expression at the mRNA and protein levels (Fig. 1). IFN- mRNA expression was barely evident in uninjured control muscle but increased substantially following injury, peaking at 5 days postinjury. In addition, IFN- protein was not evident in uninjured muscle but was strongly upregulated at 5 days postinjury. IFN- receptor mRNA was observed in uninjured muscle, and expression levels were significantly reduced at 10 days postinjury.
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expression.
We noted that the time course of IFN- expression following muscle injury was roughly similar to the time course of accumulation of F4/80+ macrophages, CD4+ T-cells, CD49b+ NK cells, and MyoD+ myoblasts. Thus we isolated each of the inflammatory cell types using antibodies coupled to magnetic beads and myoblasts using a preplating technique from muscle at 5 days postinjury. Using RT-PCR, we found that the cells isolated using the antibody-conjugated beads expressed the selected cell surface antigen, whereas the remaining nonselected cells did not (Fig. 3), indicating that that isolation procedures were specific for the targeted cell type. For the isolation of each cell type, IFN- mRNA was expressed in both the positively selected cells and the remaining nonselected cells, indicating that IFN- was expressed by each inflammatory cell type isolated, as well as myoblasts.
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receptor blocking antibody and muscle regeneration.
A previous study demonstrated that administration of exogenous IFN- can improve muscle regeneration in mice (12). We sought to determine whether blocking the action of endogenously produced IFN- would impair muscle regeneration. We administered an IFN- receptor blocking antibody daily following muscle injury and assessed the efficacy of receptor blocking using Western blot analyses of IRF-1, a transcription factor that is induced by IFN- (37). IRF-1 expression was not evident in noninjured muscle (not shown) but was upregulated at 5 days postinjury in mice treated with control antibody (Fig. 4). Mice treated with the blocking antibody demonstrated reduced induction of IRF-1.
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receptor blocking antibody exhibited a significant reduction in the formation of regenerating fibers. We also assessed cell proliferation by counting cells that had incorporated BrdU into cell nuclei and myoblast accumulation by counting MyoD+ cells. Mice treated with the IFN- blocking antibody exhibited a reduced number of proliferating cells compared with mice treated with control antibody (Fig. 4). Mice treated with the IFN- blocking antibody also exhibited a reduction in the number of MyoD+ myoblasts.
IFN- null mice and muscle regeneration.
We used IFN- null mice to further investigate the role of endogenous IFN- in muscle regeneration. Uninjured muscle from IFN- null mice demonstrated no obvious differences in muscle morphology compared with muscle from wild-type mice (Fig. 5); muscle fiber area was not different between strains (1,340 ± 80 µm2 for wild-type, 1,425 ± 123 µm2 for IFN- null). At 5 days after muscle injury, IFN- null mice demonstrated decreased number and area of regenerating fibers compared with wild-type mice (Fig. 5). At 10 days postinjury, the number of regenerating fibers was still reduced in IFN- null compared with wild-type mice. At this latter time point, trichrome staining demonstrated areas of dense connective tissue staining within the muscle of IFN- null mice (Fig. 6). There were typically two to four such areas per section that occupied the area of 1 to 8 muscle fibers. Although these fibrotic lesions were relatively infrequent in the IFN- null mice, they were never observed in muscle of wild-type mice.
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null mice and macrophage function.
Since IFN- is known to influence macrophage activation, we assessed whether macrophage accumulation or activation was altered in IFN- null mice compared with that in wild-type mice following muscle injury. At 5 days postinjury, when macrophage accumulation peaked in wild-type mice, accumulation of F4/80+ macrophages was reduced in IFN- null compared with wild-type mice (Fig. 7). Since IFN- has been reported to induce expression of MCP-1 in muscle cells (29), we tested whether impaired expression of MCP-1 in the damaged muscle of IFN- null mice contributed to the reduced macrophage accumulation. Analysis by RT-PCR demonstrated that MCP-1 is induced in both wild-type and IFN- null mice, with no difference in expression levels between strains (data not shown). To assess whether loss of IFN- alters macrophage activation following muscle injury, macrophages were isolated from injured muscle of wild-type and IFN- null mice, and mRNA expression of gene products associated with classical activation was assessed using RT-PCR. Expression of inducible nitric oxide synthase (iNOS) was reduced in IFN- null compared with that in wild-type mice (Fig. 7), whereas expression of TNF-
and IL1-β were not different between strains.
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receptor blocking antibody and muscle cells in vitro.
Previous studies have demonstrated that exogenous IFN- can influence the proliferation and fusion of muscle cells in culture (11, 17, 39). We tested whether IFN- and its receptor are expressed by muscle cells in culture and whether blocking the IFN- receptor impairs muscle cell proliferation and fusion in vitro. The C2C12 muscle cell line, derived from mouse satellite cells, was used to avoid contamination by other cell types that may express IFN-. Proliferating C2C12 myoblasts expressed IFN-, but expression was diminished in confluent myoblasts and differentiating myotubes (Fig. 8). C2C12 cells also expressed the IFN- receptor, and expression did not appear to be influenced by differentiation. When compared with cells treated with control antibody, C2C12 cells treated with IFN- receptor blocking antibody showed significantly reduced cell counts and significantly reduced cell proliferation, as measured by BrdU incorporation (Fig. 8). In addition, the IFN- receptor blocking antibody also reduced fusion of myoblasts into multinucleated myotubes.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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is required for efficient regeneration of skeletal muscle following injury. IFN- was upregulated at both the mRNA and protein levels in muscle following cardiotoxin-induced injury and was expressed by different inflammatory cells, as well as myoblasts. The major findings of the study were that administration of an IFN- receptor blocking antibody resulted in impaired induction of IRF-1, a transcription factor induced by IFN-. The blocking antibody also reduced cell proliferation and decreased formation of regenerating fibers. IFN- null mice demonstrated similar impairments in muscle healing along with development of areas of fibrosis. In addition, in vitro studies demonstrated that IFN- and its receptor are expressed in the C2C12 muscle cell line, and that the IFN- receptor blocking antibody reduced proliferation and fusion of cultured muscle cells. In total, our results indicate that endogenously produced IFN- promotes muscle regeneration, in part, through direct effects on muscle cells.
Previous studies have demonstrated that exogenous IFN- has direct effects on cultured skeletal muscle cells. Exogenous IFN- induces expression of a number of genes in muscle cells, including MCP-1, MHC II molecules, ICAM-1, complement components, and ubiquitin (20, 22, 24, 29, 34). In addition, exogenous IFN- has been shown to influence muscle cell proliferation and differentiation (11, 15, 17, 39). There are conflicting data on the effects of IFN- on muscle cell proliferation, as exogenous IFN- inhibited proliferation of human myoblasts but stimulated proliferation of rat myoblasts. Studies on human myoblast fusion have also yielded contrasting results, because different studies have reported that exogenous IFN- can either stimulate or inhibit myoblast fusion into myotubes. Our data indicated that blocking the IFN- receptor resulted in reduced mouse muscle cell proliferation and fusion, suggesting that endogenously produced IFN- promotes both processes.
Administration of exogenous IFN- can reduce fibrosis in different tissues, including lung, kidney, and liver (27, 35, 43). IFN- may exert these antifibrotic properties through direct downregulation of the production of matrix components and through blocking TGF-β-mediated increases in matrix synthesis (13, 40). In mouse skeletal muscle, administration of exogenous IFN- at 1 or 2 wk after laceration injury was shown to reduce fibrosis, increase formation of regenerating fibers, and improve muscle function (12). Exogenous IFN- also inhibited growth of fibroblasts derived from muscle and inhibited expression of proteins associated with fibrosis. These data indicate that exogenous IFN- can enhance healing and limit tissue fibrosis. Our data extend these findings and indicate that endogenously produced IFN- promotes muscle regeneration by limiting fibrosis and by promoting formation of new muscle fibers.
Although many studies indicate that IFN- reduces tissue fibrosis, other investigations have demonstrated negative effects of IFN- on skeletal muscle. Transgenic mice that constitutively overexpress IFN- specifically at the neuromuscular junction were developed as a model for myasthenia gravis (31). These mice developed an age-associated necrotizing myopathy in which the acetylcholine receptor appears not to be the primary target. The pathological changes induced by constitutive overexpression of IFN- may have been the result of direct effects on muscle cells or damage mediated by inflammatory cells. In another study, IFN- has been shown to contribute to the catabolic state induced by massive trauma; IFN- knockout mice demonstrated reduced muscle protein degradation following burn trauma compared with that of wild-type mice (23). Thus IFN- may negatively impact skeletal muscle when present at high concentrations for sustained periods of time, whereas lower levels acting over shorter periods of time appears to promote muscle healing.
IFN- induces cellular responses by binding to its specific extracellular membrane receptor (9). Such binding induces activation of the tyrosine kinases JAK-1 and JAK-2, leading to the phosphorylation of the IFN- receptor subunit-1. This leads to docking of STAT-1 and its phosphorylation, which then leads to translocation of STAT-1 to the nucleus, where it binds to gamma-activated sequence elements to regulate expression of numerous genes, including IRF-1, iNOS, and suppressor of cytokine signaling (SOCS-3), the latter of which has been reported to play a role in myoblast fusion (33). Interestingly, IFN- is generally viewed as an antiproliferative factor, and exogenous IFN- indeed appears to reduce proliferation in cells that express STAT-1 (4, 28). However, the same concentrations of IFN- that impair proliferation of STAT-1-expressing cells can increase the proliferation of STAT-1-deficient cells. These data indicate that IFN- has the capability to either positively or negatively influence cell proliferation depending on whether intracellular signaling is dominated by STAT-1-dependent or -independent pathways.
Another mechanism by which IFN- could influence muscle regeneration is through its effects on macrophage activation. IFN- is known to promote classical activation of macrophages, resulting in increased production of inflammatory cytokines, iNOS, and reactive oxygen species. Our data indicate that mRNA expression of iNOS is reduced in macrophages isolated from injured muscle of IFN- null mice compared with that of wild-type mice, whereas expression of other markers of classical activation (TNF-, IL1-β) was not altered. Previous investigators have reported that iNOS may play an important role in healing of skin wounds (16, 42); whether iNOS plays a similar role in muscle healing remains to be determined. Additionally, a recent study demonstrated that classical macrophage activation can enhance the ability of macrophages to stimulate proliferation of muscle satellite cells (1). Thus we speculate that IFN- could stimulate myoblast proliferation and muscle regeneration indirectly through macrophage activation as well as through direct effects on satellite cells.
In conclusion, our data indicate that endogenous production of the inflammatory cytokine IFN- is required for efficient skeletal muscle regeneration, in part, through direct effects on muscle cells. These data extend previous findings that exogenous IFN- promotes muscle regeneration and reduces fibrosis. These data are also consistent with reports demonstrating that reducing the inflammatory response with nonsteroidal anti-inflammatory agents impair healing of skeletal muscle following injury (3, 32). IFN- may play a key role in regulating the activity of inflammatory cells, muscle cells, and fibroblasts during muscle healing, and further investigation into the mechanisms by which this occurs is warranted.
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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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