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Proc Natl Acad Sci U S A. Sep 9, 2008; 105(36): 13662–13667.
Published online Aug 29, 2008. doi:  10.1073/pnas.0805365105
PMCID: PMC2533246
Physiology

Mechano-regulated Tenascin-C orchestrates muscle repair

Abstract

Tenascin-C (TNC) is a mechano-regulated, morphogenic, extracellular matrix protein that is associated with tissue remodeling. The physiological role of TNC remains unclear because transgenic mice engineered for a TNC deficiency, via a defect in TNC secretion, show no major pathologies. We hypothesized that TNC-deficient mice would demonstrate defects in the repair of damaged leg muscles, which would be of functional significance because this tissue is subjected to frequent cycles of mechanical damage and regeneration. TNC-deficient mice demonstrated a blunted expression of the large TNC isoform and a selective atrophy of fast-muscle fibers associated with a defective, fast myogenic expression response to a damaging mechanical challenge. Transcript profiling mapped a set of de-adhesion, angiogenesis, and wound healing regulators as TNC expression targets in striated muscle. Expression of these regulators correlated with the residual expression of a damage-related 200-kDa protein, which resembled the small TNC isoform. Somatic knockin of TNC in fast-muscle fibers confirmed the activation of a complex expression program of interstitial and slow myofiber repair by myofiber-derived TNC. The results presented here show that a TNC-orchestrated molecular pathway integrates muscle repair into the load-dependent control of the striated muscle phenotype.

Keywords: damage, expression, extracellular, gene therapy, myogenesis

Tenascin-C (TNC) is an extracellular matrix protein that assembles from differently spliced isoforms (1, 2). TNC is expressed only in actively remodeling musculoskeletal tissue, subject to high mechanical stress (3). This expression is load-dependent and reversible (46). Microdamage may contribute to the mechano-regulation of TNC expression (6).

TNC exerts a strong anabolic and proliferative effect on interstitial and myogenic cells in culture (1, 710). This is mediated by TNC's de-adhesive property that relieves the growth inhibition of substrate attachment (8). The transition to an intermediate adhesive state may facilitate the expression of genes specific for tissue repair and adaptation (8). This view is supported by the de novo accumulation of TNC in muscle connective tissue after damaging muscle loading and the correlation of ectopic TNC protein with the growth-related gene expression during muscle fiber regeneration (5, 11). These observations suggest that TNC-mediated de-adhesion contributes to cell repair in mechano-sensitive tissues.

The functional role of TNC in tissue morphogenesis remains unclear, mainly because transgenic mice engineered for TNC deficiency show only subtle phenotypic defects (10, 12). The pathologies in transgenic mouse lines include reduced neovascularization and cell migration in injured muscle tissue and mechanically stressed corneal wounds (1, 7, 8, 10, 13, 14). The aberrations in TNC-deficient mice could be somewhat masked by the permissive expression of an abnormal TNC variant (15). This ambiguity may relate to the transgenic strategy of abolishing the production of extracellular TNC protein by disrupting the N-terminal signal sequence for protein export (12, 16). This genetic manipulation may leave downstream translation initiation sites intact for the production of shortened TNC variants (15, 16). Proteins can exit the cytoplasm of cells residing in mechanically stressed tissues by diffusion after plasma membrane disruption (17). The implications of such a mechanism for TNC in tissue repair and the minor phenotype of transgenic mice with deficient TNC secretion are not understood.

We have adopted a multilevel approach that monitors damage-related changes in muscles of both TNC-deficient and TNC knockin mice. Leg muscles are suitable for this approach because they are amenable to physiological modulation of their mechanical activity (18), and they are accessible to somatic transgenesis (19). The pathways of TNC action were identified by monitoring transcript expression of muscle-relevant gene ontologies (GOs) in antigravitational muscle. We focused on deregulated gene expression reflected in the differences between the mechano-responsiveness of transcript levels in the soleus muscle in WT and transgenic littermates (18, 20), bearing in mind the possible production of an aberrant TNC variant with muscle damage. The control of selected TNC-dependent gene products was verified ad hoc with muscle fiber-targeted somatic knockin experiments.

Results

TNC Isoform Expression Distinguishes Muscle from Noncontractile Tissues.

In WT mice, leg muscles variably expressed the small 200-kDa TNC isoform (Fig. 1A), whereas in lung, brain, and skin, the large 250-kDa TNC predominated (Fig. 1B). TNC expression was blunted in the noncontractile tissues of transgenic littermates. However, a 200-kDa TNC-immunoreactive band remained detectable at a 10-fold lower level in the muscle tissue of TNC-deficient mice (Fig. 1B).

Fig. 1.
Preserved small TNC isoform expression in TNC-deficient mice. (A) TNC expression in noncontractile tissues. (B) Different leg muscles of WT and TNC-deficient mice. Arrows indicate the large 250-kDa and the small 200-kDa TNC isoforms, detected by monoclonal ...

TNC-Deficient Mice Demonstrate Fast-Muscle Fiber Atrophy.

One-year-old, TNC-deficient mice demonstrated reduced mass of the pure fast-type muscles, tibialis anterior and extensor digitorum longus (Fig. 2A). At this age, no genotypic difference was seen in the mixed slow/fast musculi soleus. Quantitative microscopic analysis demonstrated a selective reduction of mean cross-sectional area (CSA) for fast-type muscle fibers in the extensor digitorum longus and soleus muscles of TNC-deficient mice (Fig. 2B). The musculi solei of TNC-deficient mice showed a significant slowing of muscle contractions (Table 1).

Fig. 2.
Fast-fiber atrophy in TNC-deficient mice. Mean ± SE of the mass (A) and CSA (B) of fiber types in fast (EDL, TA) and mixed slow/fast muscle (SOL) of WT and TNC-deficient mice at 1 and 2 years of age. *, P < 0.05 between genotypes of same ...
Table 1.
Genotype effect on contraction in soleus muscle

Atrophy of fast soleus muscle fibers in TNC-deficient mice was progressive and became evident at the whole muscle level after two years of age (Fig. 2 A and B).

Transcript Adjustments with TNC Deficiency.

The contribution of expressional reprogramming to fast-fiber atrophy in the soleus muscle was evaluated. Transcript profiling of muscle-relevant factors identified general up-regulated mRNA levels in musculi solei of one-year-old, TNC-deficient cage controls (P = 4 × 10−15). The major theme was the up-regulation of transcripts for GOs associated with the myofiber compartment, adhesion, and angiogenesis [Table 2 and supporting information (SI) Table S1], including factors associated with slow fibers. At two years of age, a majority of genotypic differences in muscle mRNAs were preserved except for those associated with myofibers.

Table 2.
Shifted transcript expression with TNC deficiency

TNC-Related, Mechano-Responsiveness of Muscle Gene Expression.

The soleus muscles of TNC-deficient and WT mice were mechanically challenged by reloading after 7 d of deconditioning by hind limb suspension. The mechanical stimulus selectively induced damage of soleus muscle fibers in the TNC-deficient animals (Fig. 3A).

Fig. 3.
Genotype differences in the reloading response. (A) Mean + SE percentage of damaged soleus muscle fibers in cage control (CTL) and 1 d reloaded (R1) WT and TNC-deficient mice. *, P < 0.05 vs. cage controls by using two-factor ANOVA (genotype × ...

In the 1 d reloading response of one-year-old mice, 155 transcripts showed a significant TNC genotype dependency (Table S2). Multicorrelation testing identified two main clusters of coregulated mRNA levels (Fig. 3B). Within the cluster of coincidentally up-regulated RNAs, discrete GOs assigned to de-adhesion, angiogenesis, and wound healing were enriched (Table S3). Conversely, factors associated with myofibers were concentrated in the cluster of down-regulated RNAs. The main exceptions were three up-regulated myogenic regulators, myogenin (myoG), serum response factor (SRF), and myocyte enhancer factor-1 (MEF2A).

The comparison with cage controls revealed that reloading inverted the transcript expression ratios between genotypes (P = 1 × 10−12) (Table S3) except for GOs relating to myofibers. This “mirror effect” correlated with the expression of TNC mRNA, which was selectively elevated in musculi solei of TNC-deficient mice after reloading (mean r2 = 0.92) (Fig. 3C).

Proof-of-Concept for the Myocellular TNC-Signaling Pathway.

Muscle fiber-targeted overexpression of the chicken TNC homologue (chTNC) in TNC-deficient mice was carried out to validate TNC-mediated expression control at the protein level. The pure fast-type muscle tibialis anterior was studied. We looked for key regulatory factors with deregulated transcript expression in TNC-deficient mice relative to fast-type muscle fibers. The master regulators of myogenesis in slow- and fast-muscle fibers, myoG, and myogenic differentiation 1 (myoD) (21), and the proliferation regulator cyclin A (22) met these criteria (Fig. 3C).

The exogenously introduced 190-kDa chTNC was exclusively overexpressed in the right tibialis anterior muscle after transfection with a constitutively active expression plasmid but was not overexpressed in empty vector transfected left controls. Expression was maximal 2 d after transfection and maintained for 1 week (Fig. 4 A and B). Quantitative immunoblotting of muscle pairs identified a transient increase of cyclin A and myoG protein levels at 2 d (but not 1 d) after knockin (Fig. 4 C and E). MyoD protein levels were not significantly affected by TNC overexpression (Fig. 4D).

Fig. 4.
Proof-of-concept on TNC-dependent expression control. Time course of protein level adjustments of selected TNC targets in TA muscle of TNC-deficient mice after TNC knockin. Right muscles were transfected with expression plasmid for chicken TNC (pcDNAI-chTNC). ...

Induced Expression of the Small 200-kDa TNC-Related Protein in Injured Muscle.

Expression of the 200-kDa TNC-immunoreactive protein (Figs. 4A and and55A) and muscle damage (data not shown) were readily detectable on both muscle sides of electrotransfected musculi tibialis anterior in TNC-deficient mice. In WT mice, a 3-fold up-regulation of both the small and the large TNC isoform was evident after electrotransfer (Fig. 5B). Expression of the small TNC-immunoreactive protein was selectively induced at the periphery of ≈10% of soleus muscle fibers in TNC-deficient mice after reloading (Fig. 5C and Fig. S1).

Fig. 5.
TNC-related protein expression in TNC-deficient mice after muscle damage. (A and B) Immunoblots visualizing expression of the 200-kDa and 250-kDa TNC isoforms (A) in muscle as a function of empty vector electrotransfer in TNC-deficient and WT mice (B ...

Discussion

The role of TNC in regenerative processes has been a riddle because transgenic mice with targeted ablation of TNC secretion were found to have no obvious phenotype (10, 12, 23). Our findings shed light on this matter. We find abnormal myogenesis and atrophy of fast-differentiated myofibers of locomotor muscles in the original TNC-deficient mouse strain of Faessler et al. (12). This pathology was related to the blunted expression of the large TNC isoform in TNC-deficient mice and to the unexpected expression of a TNC-related protein upon muscle fiber damage.

Assumption Bias.

Our experiments led us to suspect the possible production of an atypical TNC protein in the transgenic mouse line under study (12, 15). Doubt arose with immunoblotting experiments that demonstrated induced expression of a 200-kDa protein with muscle reloading and electropulsing of two different leg muscles (Fig. 5). Based on its antigenicity and size, this protein was indistinguishable from the small TNC isoform. In TNC-deficient mice, functional similarity of this protein to the small TNC isoform is suggested by the inversion of genotype differences of transcript expression in cage controls after reloading when expression of the 200-kDa TNC protein was elevated (Figs. 3B and and55C). This notion is corroborated by the corresponding selective enhancement of TNC mRNA levels in TNC-deficient mice with reloading (Fig. 3C). Western blot experiments excluded any contribution from the related, and similarly sized, Tenascin-W isoform (Fig. S2).

We reasoned that the expression of a TNC-related protein in muscle tissue is the consequence of an alternative in-frame start codon in the modified TNC gene sequence and protein release from damaged cells via a secretion-independent mechanism (17). DNA sequencing of the modified TNC gene identified an in-frame start codon shortly after the ablated signal peptide. The context of this start codon meets the consensus requirements for translation initiation (Fig. S3). The resulting protein would not be easily distinguishable from the processed muscle-specific 200-kDa TNC isoform (Figs. 1A and and55B) because the anticipated cleavage site of the TNC signal peptide during secretion is only a few amino acids away from the alternative start codon (Fig. S3). Damage of the sarcolemma, with reloading of deconditioned soleus muscle and/or electropulsing (20, 24), would allow the release of a TNC variant from muscle fibers. This conclusion is compatible with the observation that the expression of the large 250-kDa TNC isoform, which relies on active secretion from interstitial cells (2), is blunted in leg muscles of the transgenic line (Fig. 5 A and B).

TNC-Dependent Muscle Phenotype.

Our multilevel approach identified a discrete shift of transcript expression in the mixed soleus muscle of TNC-deficient mice toward the characteristics of slow fibers (Table 2 and Table S1). This was accompanied by correspondingly reduced fast-fiber volume and slowed contraction (Table 1). We also noted that the reduction in fast-fiber, CSA in the belly portion of the soleus muscle was not matched by the differences in muscle mass in one-year-old TNC-deficient mice (Fig. 2). Together with the observation on the elongated tibial bone, which defines soleus muscle length (Table 1), this unmatched reduction indicates a complex role for TNC in determining the architecture of the musculoskeletal system. Until now, this complex role has been overlooked (23).

Mapping of TNC-Expression Targets.

The marked TNC genotype-specific up-regulation of gene messages on reloading of the soleus muscle identified a series of targets for TNC signaling in skeletal muscle (Table S3). The concurrent up-regulation of mRNAs for wound healing, de-adhesion, and angiogenesis, along with the regulators of myogenesis (myoG, SRF, and MEF2A), provided direct evidence for regulation of both interstitial and myogenic processes by TNC. The molecular analysis of muscle fiber-targeted overexpression of the chTNC confirmed this association. It identified the TNC-modulated up-regulation of the master regulator of slow-type myogenesis, myoG, and the regulator of interstitial cell proliferation, cyclin A (Fig. 4 C and E) (21, 22). This regulation opposes the down-regulation of the governor of fast-muscle gene expression, myoD (21).

Damage-Induced Coordination of Myocellular and Interstitial Repair via TNC Isoforms.

Muscle loading induces a pleiotropic response (25). The functional implications of this complex process are largely unknown. Our results imply that a damage-inducible TNC pathway coordinates the myocellular and interstitial response to mechanical fiber damage. The observations connect the regulation of small and large TNC isoforms to the differential control of slow- and fast-type myogenesis and cell proliferation. The up-regulation of the small TNC-related protein after muscle fiber damage (by reloading and somatic transgenesis) relates to the promotion of the slow myogenic program via myoG- and cyclin A-activated cell proliferation. Conversely, the production of the putative secreted large TNC isoform (which is absent in TNC-deficient mice) is associated with enhanced transcript expression of the fast-type myogenic factor, myoD. These observations are compatible with the idea that a blunted, fast myogenic program explains the deterioration of the fast-type characteristics of leg muscles in TNC-deficient mice.

Mechanically Induced TNC Production in Muscle and Repair.

Expression of the de-adhesive TNC protein is believed to be a requirement for repair of mechanically stressed cells. De-adhesion allows relief from strain (3, 8). We observed that TNC-dependent RNA control factors are involved in de-adhesion, myogenesis, and wound healing after the mechanical challenge of reloading. This observation indicates that de-adhesion occurs in striated muscle tissue (Table S3). The TNC-modulated control of major regulators of cell proliferation and myofiber differentiation, myoG and cyclin A, provides important insight. The observed time course of TNC-promoted up-regulation (Fig. 4 C and E) mirrors the retarded cell recruitment after myocardial injury in TNC-deficient mice (13). This indicates that damage-induced TNC production governs the pace of muscle fiber repair by modulating interstitial and myogenic cell activation.

Cycles of microdamage and repair may contribute to the basal muscle turnover of skeletal muscles (26). Our observations imply a role of load-regulated TNC up-regulation in this damage-repair cycle. This is indicated by the increased susceptibility of muscle to mechanical damage in TNC-deficient mice (Fig. 3A) and the atrophy of fast fiber during the mouse lifespan (Fig. 2). Interestingly, fast-type muscle fibers show preferential vulnerability to reloading damage in rodents (27) and ectopic TNC staining with atrophy and age-induced atrophy in humans (sarcopenia) (28). These arguments point to deregulated TNC expression as a possible cofactor for the etiology of sarcopenia in humans.

Conclusions.

TNC is part of a pleiotropic pathway that protects fast-muscle fiber mass from the deleterious consequences of mechanically induced microdamage. This insight into the biomechanical control of the muscle phenotype is relevant for reducing or healing musculoskeletal injuries.

Materials and Methods

Bio-Reagents.

Endotoxin-free plasmids for the CMV-driven expression of the 190-kDa chicken TNC isoform, pcDNAI-chTNC (9), and empty vector (pcDNAI), were isolated according to industrial standards at Plasmidfactory (Bielefeld, Germany). Established monoclonal antibodies from rat (mTN12) and mouse hybridomas (TN20) were used to detect TNC, myosin heavy chain, and myoG (11, 29). Commercial antibodies were deployed to detect the other proteins including cyclin A (BD Transduction Laboratories), myoD, and myoG (Santa Cruz Biotechnology). HRP-coupled secondary antibodies were from Sigma-Aldrich and ICN.

Animals.

Male TNC-deficient mice of the 129/SV strain, with the targeted insertion of a β-lactamase cassette in the NcoI site of exon 2 of the TNC gene (12), were used for the study. Animals were derived from the original strain and back crossed with WT 129/SV mice. Genotype was determined with PCR on tail DNA (7). For details see Fig. S1.

Cage Controls and Reloading of the Soleus Muscle.

WT and TNC-deficient mice were acclimatized to housing in single cages for 1 week before they were assigned to the reloading group (R1) or the cage control group (CTL). Hind limb muscles were deconditioned for 7 d by unloading, subsequent reloading, and harvesting of muscle pairs (18). Unloading reproduced the reported reduction in whole-body mass and soleus muscle mass. All procedures were approved by the Animal Protection Commission of the Canton Bern, Switzerland.

Aging.

Animals were housed in standard cages in cohorts with regular chow and water ad libitum. One week before the experiments, the mice were acclimatized to single cages.

Muscle-Targeted TNC Knock-In.

Overexpression experiments with the CMV-driven plasmid were carried out in a paired design: empty pcDNAI plasmid was electrotransferred into the left tibialis anterior muscle of TNC-deficient mice, and pcDNAI-chTNC was transfected into the contralateral right muscle. Electrotransfer was carried out with modifications as described (19). In brief, 30 μg of plasmid in 30 μl of 0.9% NaCl was injected into the central portion of the muscle and electropulses (3 trains of 100 pulses of 100 μs each, at 50 mA) were delivered with needle electrodes by using a GET42 electropulser (Electronique Informatique du Pilat). Transfected muscle portions were collected after 1, 2, 4, and 7 d (18). In additional experiments, tibialis anterior and extensor digitorum longus muscles were harvested 7 d after transfection with empty plasmid.

Muscle Fiber Structure.

Composition and mean CSA of slow- and fast-type muscle fibers and muscle fiber damage were determined with standard morphometry on hematoxylin-stained cross-sections from the muscle belly portion after immunostaining for fast- and slow-type myosin heavy chains (11, 18). On average, 224 muscle fibers were counted per section.

In Situ Testing of Muscle Contractility.

Contractile characteristics of isolated soleus muscles were determined by using the method of Andrade et al. (30) with modifications, by using a muscle tester operated by a PowerLab system (ADInstruments). Single twitch and maximal tetanic contractions were evoked at optimal length by stimulation at 1 Hz for 0.4 ms and 60 Hz for 4 s, respectively, with 10 V from an Ion Optix Myopacer (IonOptix). Fatigue was determined from a drop below 50% of the original force of repeated tetanic contractions every 4 s.

Transcript Profiling.

Microarray experiments were carried out on total RNA by using a validated, custom-designed ATLASTM cDNA nylon filter holding cDNA probes for 222 muscle-relevant mRNAs (18). The curation of transcripts to a GO was based on the information available through the electronic literature (http://www.expasy.org/sprot/ and http://www.ncbi.nlm.nih.gov/sites/entrez). Data sets and platform design were deposited under accession codes GSE8551, GSE8549, GSE8550, and GSE8552 at Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo).

Normalized microarray data were analyzed for differentially expressed RNAs by using Significance Analysis of Microarrays (SAM) software (18). Genotype differences in the mechano-responsiveness (the reloading response) of transcript expression were evaluated by using the R1 vs. CTL ratio of significantly affected transcripts after centering to the mean of cage controls. The global pattern of the reloading response was visualized with hierarchical cluster analysis of median-centered R1 vs. CTL ratios (11). Global themes of coregulation were assessed by a sign test verifying the enrichment of codirectional transcript level alterations in a given GO between genotypes and/or with reloading (Microsoft Excel). Deregulated transcripts were identified from a shifted or inverted reloading response (R1 vs. CTL) between TNC-deficient and WT mice compared with cage controls.

Immunoblotting.

Sample preparation, SDS/PAGE, and quantitative immunoblotting was carried out as described (5), except that ultra-sensitive ECL was used (Supersignal-Femto, Pierce).

Statistics.

Individual data were assembled in Microsoft Excel. Probability-based statistical tests were carried out with Statistica (StatSoft). Statistical significance was assumed at P < 0.05. Trends were assumed at 0.05 ≤ P < 0.10.

Supplementary Material

Supporting Information:

Acknowledgments.

This study was supported by the Swiss National Science Foundation and the Association Française Contre les Myopathies. We thank Ruth Chiquet-Ehrismann and Matthias Chiquet (Friedrich Miescher Institute, Basel, Switzerland) for providing bioreagents.

Footnotes

Conflict of interest statement: We report a potential conflict of interest related to the preparation of a provisional patent application.

Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession nos. GSE8549, GSE8550, GSE8551, and GSE8552).

This article contains supporting information online at www.pnas.org/cgi/content/full/0805365105/DCSupplemental.

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