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GROWTH, DIFFERENTIATION, AND APOPTOSIS
Laboratory of Muscle Biology and Sarcopenia, Division of Exercise Physiology, West Virginia University School of Medicine, Morgantown, West Virginia
Submitted 11 February 2008 ; accepted in final form 22 May 2008
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ABSTRACT |
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25% and 30%, respectively, were shown in plantaris muscle wet weight compared with that shown in the contralateral control muscle. The number of BrdU-positive nuclei increased similarly in loaded plantaris muscles from LZR and OZR. Myogenin, MyoD, and Akt protein expressions were lower in control muscles of OZR than in those of the LZR, but they were all elevated to similar levels in the loaded plantaris muscles of OZR and LZR. These data indicate that metabolic syndrome may reduce satellite cell proliferation, and this may be a factor that contributes to the reduced mass in control muscles of OZR; however, satellite cell proliferation can be restored with compensatory loading in OZR. metabolic syndrome; muscle hypertrophy; muscle stem cells; muscle transcription factor
The lower skeletal muscle mass in the OZR appears to be partly accounted for by an altered balance between protein synthesis and degradation in this model of metabolic syndrome (4, 16). However, it has also been observed that there is a decrease in nucleic acid content in the muscles of the OZR compared with that shown in the LZR (16). Replacement of nuclei that are lost during normal turnover, as well as the maintenance of nuclear content in adult muscle, is a primary responsibility of muscle satellite cells. Muscle satellite cells are normally quiescent myogenic precursor cells found between the basal lamina and the sarcolemma of a muscle fiber (1). However, these cells can proliferate in response to a variety of stimuli, and they are responsible for maintenance of the nuclear- to-cytoplasmic relationship in muscle. Furthermore, postnatal muscle growth and hypertrophy of skeletal muscle critically depend on the proliferation and differentiation of muscle satellite cells (1, 25). It is possible that a decrease in satellite cell proliferation could contribute to the decrease in nucleic acid content and skeletal muscle mass observed in the OZR.
Mechanisms that may contribute to lower satellite cell proliferation and differentiation in muscles of the OZR could include decreases in the expression levels of myogenic regulatory factor proteins. Myogenic regulatory factors are muscle-specific helix-loop-helix transcription factors that regulate muscle-specific genes (12, 25). Myogenic differentiation factor D (MyoD) and myogenin are myogenic regulatory factors that are expressed in activated satellite cells, and they are necessary for satellite cell proliferation and differentiation (12, 37). MyoD and myogenin are reduced during muscle atrophy and in models of diabetes (3, 13), although it has not been determined whether this corresponds to reduced satellite cell proliferation or differentiation in models of metabolic syndrome. We hypothesized that a decrease in the protein expression of MyoD and myogenin might result in lower satellite cell proliferation and/or differentiation and lead to lower muscle mass in the OZR model of metabolic syndrome vs. that shown in the LZR phenotype.
Another possible mechanism for disrupted satellite cell proliferation is deregulated protein kinase B/Akt (Akt) signaling. Control of the Akt signaling pathway is essential for muscle growth and hypertrophy [previously reviewed (7, 19)]. Furthermore, a lower level of activated Akt is associated with attenuated increases in muscle hypertrophy under conditions such as aging (7, 19). Akt and specifically Akt2 are essential for proliferation and differentiation of skeletal muscle satellite cells (7, 8). In the OZR model, there is a reduced protein expression of Akt2 and reduced activity levels of both Akt1 and Akt2 compared with that shown in the LZR (24). These findings underscore the possibility that Akt signaling may play an important role in the control of satellite cell proliferation and differentiation in muscles of the OZR.
Although the skeletal muscles of the OZR are smaller than those in the LZR, to the best of our knowledge no study has evaluated whether muscles in the OZR have attenuated hypertrophy in response to loading. Although the OZR is significantly less active than the LZR (9), OZRs have much greater body mass, and this should provide a greater stimulus for muscle growth on the weight-bearing muscles. Nevertheless, a previous study from our laboratory in which the daily activity of the OZR was increased through daily treadmill running demonstrated no increase in the size of their skeletal muscles (18). These findings suggest that there may be an underlying deficit in the ability of skeletal muscle to respond to increased loading in the OZR model of metabolic syndrome.
The purposes of this study were to determine 1) whether there was a decrease in the number of satellite cells in the skeletal muscles of the OZR compared with that shown in the LZR, 2) whether satellite cell proliferation is attenuated in OZR compared with that shown in the LZR in control muscle, 3) whether satellite cell proliferation is attenuated in OZR compared with that shown in the LZR in loaded muscle, and, 4) whether the skeletal muscles of the OZR are able to hypertrophy in response to loading. Furthermore, because muscle loading directly activates Akt (31) and myogenic regulatory factor signaling (2, 26), Akt, MyoD, and myogenin protein expression levels were measured. We hypothesized that Akt and myogenic regulatory factor protein expression would be rescued with compensatory hypertrophy in the OZR and enable a restoration of satellite cell proliferation to levels similar to those in lean animals.
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METHODS |
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Compensatory loading protocol.
To achieve compensatory hypertrophy of the plantaris muscle, synergist denervation of the soleus and gastrocnemius muscles was used as previously described (14). Briefly, the distal branches of the tibial nerve were transected, thus removing the innervation to the soleus muscle and both heads of the gastrocnemius muscle. The severed nerve endings were sutured onto the biceps femoris muscle to prevent reinnervation back to the original muscles (14). This placed a compensatory load on the plantaris muscle. The contralateral limb received a sham surgery in which the branches of the tibial nerve were identified but not severed, and this served as an internal control for each animal. All procedures were performed under aseptic conditions. The animals recovered quickly and were alert and walking within 15 min after surgery. Loading occurred for 7 or 21 days.
Bromodeoxyuridine implantation. A time-released 5-bromo-2-deoxyuridine (BrdU) pellet (21-day release, 0.22 µg BrdU·g body mass–1·day–1; Innovative Research, Sarasota, FL) was placed subcutaneously on the dorsum of the back of each animal. BrdU is a thymidine analog and is incorporated in nuclei during DNA synthesis. Skeletal muscle nuclei are postmitotic and cannot incorporate BrdU into their DNA. In contrast, satellite cells can incorporate BrdU during proliferation. Therefore, BrdU-positive nuclei located under the basal lamina can be identified as satellite cells that have proliferated, migrated, and become incorporated into a muscle fiber (1). Therefore, BrdU was used to identify satellite cells or muscle precursor cells that had proliferated during the 7- or 21-day period of muscle loading-induced hypertrophy. Only the BrdU-positive nuclei within the basal lamina were quantified. The BrdU labeling index was calculated as the number of BrdU-labeled myonuclei·total myonuclei–1·100. This provided an index of satellite cell proliferation.
Tissue collection. The plantaris muscles were collected 7 days (n = 6 LZR-7 and n = 6 OZR-7) or 21 days (n = 6 LZR-21 and n = 6 OZR-21) after the surgical denervation of the synergists. The animals were 12 wk old at time of tissue collection. The rats were anesthetized with ketamine hydrochloride (9 mg/100 g body wt) and xylazine hydrochloride (1 mg/100 g body wt) intraperitoneally, and the plantaris muscles from each limb were removed and frozen in isopentane, cooled to the temperature of liquid nitrogen, and stored at –80°C until further analysis. In addition, a midbelly section of each muscle was fixed in 10% formalin and embedded in paraffin. Finally, blood was collected by means of cardiac puncture and analyzed for blood glucose, and plasma was prepared for insulin measurements as described by the manufacturer (Crystal Chem, Downers Grove, IL).
Immunoblot protein analysis. Total protein homogenates were prepared in lysis buffer (20 mM Tris, pH 7.5, 150 mM NaCl, 1% Nonidet P-40, 0.5% sodium deoxycholate, 1 mM EDTA, 0.1% SDS) with the addition of a protease inhibitor (Sigma, St. Louis, MO). The protein contents of muscle homogenates were quantified in duplicate by using bicinchoninic acid reagents (Pierce, Rockford, IL) and BSA standards. The mitochondria-free cytosolic protein fraction was isolated as previously described (33) and used for immunoblotting for apoptosis-inducing factor (AIF). AIF was used as an index of mitochondria permeability and release of proapoptotic factors to the cytosolic protein fraction. Soluble protein (50 µg) was boiled for 4 min at 100°C in Laemmli buffer and separated on a 4–12% gradient polyacrylamide gel (Invitrogen). The gels were blotted to nitrocellulose membranes (Bio-Rad, Hercules, CA) and stained with Ponceau red (Sigma) to confirm equal loading and transfer of proteins to the membrane.
The membranes were then blocked in 5% nonfat milk in Tris-buffered saline containing 0.05% Tween 20 and probed with antibodies to Akt, Akt1, Akt2 (Cell Signaling Technology), MyoD, or myogenin (Santa Cruz Biotechnology, Santa Cruz, CA). To determine whether apoptotic signaling was enhanced in control muscles of OZR, the membranes were probed with antibodies to AIF, apoptotic protease-activating factor 1 (Apaf-1), apoptosis repressor with a caspase recruitment domain (ARC), and Bcl-xL/Bcl-2-associated death promoter (BAD; Santa Cruz Biotechnology). As a further confirmation of equal loading and blotting of the proteins, the membranes were also probed for β-tubulin or GAPDH (Abcam, Cambridge, MA). Secondary antibodies were conjugated to horseradish peroxidase (Chemicon), and the signals were developed by chemiluminescence (ECL advance, Amersham Biosciences). The signals were visualized by exposing the membranes to X-ray films (BioMax MS-1; Eastman Kodak, Rochester, NY), and digital records of the films were captured with a Kodak 290 camera. The resulting bands were quantified as optical density x band area by a one-dimensional image analysis system (Eastman Kodak) and expressed in arbitrary units normalized to β-tubulin or GAPDH (Abcam).
Immunofluorescent staining. Paraffin-embedded, 7-µm-thick, muscle cross sections from loaded and control plantaris muscles were deparaffinized in xylene, followed by rehydration in graded ethanol washes, and then rinsed in distilled water. The tissues sections were incubated in an antigen retrieval buffer (10 mM sodium citrate, 0.05% Tween 20, pH 6.0) for 30 min at 95°C, washed in PBS, and then blocked in 1.5% goat serum in PBS at 37°C for 30 min. Sections were then incubated with an anti-BrdU mouse monoclonal antibody (BD Pharmingen, San Diego, CA) followed by an anti-mouse Alexa 488 (Invitrogen). Negative control experiments were done by omitting the BrdU antibody from the tissue sections. The basal lamina was identified with a primary antibody to anti-laminin (D18; Hybridoma Bank, Univ. of Iowa, Iowa City, IA) followed by a rhodamine-conjugated secondary antibody (Santa Cruz Biotechnology). Only the BrdU-positive nuclei within the basal lamina were quantified. The BrdU labeling index was calculated as the number of BrdU labeled nuclei·total nuclei–1·100. This provided an index of satellite cell proliferation.
Pax7 antibody (Developmental Studies, Hybridoma Bank, Univ. of Iowa) was used to determine the number of satellite cells in the control muscles (40). Because the formalin fixation interfered with the Pax7 antibody, 7-µm cross sections were obtained from frozen midbelly sections of the muscle as previously performed in our laboratory (34). Briefly, the sections were air dried at room temperature, fixed in ice-cold methanol-acetone (1:1) for 10 min, rinsed in PBS, and permeabilized in 0.2% Triton-X in 0.1% sodium citrate. The sections were incubated for 30 min in 1.5% goat serum at 37°C and then incubated with a primary antibody to Pax7 followed by Alexa 488. The tissue sections were then probed with anti-laminin mouse IgG2a (2E8; Hybridoma Bank, Univ. of Iowa) followed by a rhodamine-conjugated secondary antibody (Santa Cruz Biotechnology).
Immunoblot analysis was completed on six nonoverlapping tissue cross sections (x40 magnification). Three cross sections were examined in each muscle. Myonuclei were only counted for analysis if they resided within the basal lamina. Pax7-positive nuclei were identified as quiescent satellite cells, because neither myonuclei nor activated/differentiated satellite cells express Pax7 (40). In addition, skeletal muscle nuclei are postmitotic; therefore, any nuclei residing under the basal lamina that were BrdU positive were identified as proliferated satellite cells (1). The BrdU labeling index was calculated as the number of BrdU-labeled myonuclei·total myonuclei–1·100, and this was used as an index of satellite cell proliferation.
In situ TdT-mediated dUTP nick end labeling staining. Apoptotic nuclei were assessed from muscle cross sections via a TdT-mediated dUTP nick end labeling (TUNEL) assay. Frozen sections (10 µm thick) were cut in a freezing cryostat at –20°C from plantaris muscle cross sections. Apoptotic nuclei were identified by a fluorometric TUNEL detection kit (Roche Applied Science, Indianapolis, IN) according to the manufacturer's instructions for muscle cross sections. Briefly, tissue sections were fixed in 4% paraformaldehyde in PBS, pH 7.4, at room temperature for 20 min, permeabilized with 0.2% Triton X-100 in 0.1% sodium citrate at 4°C for 2 min, and incubated with fluorescein-conjugated TUNEL reaction. Negative control experiments were done by omitting the TdT enzyme in the TUNEL reaction mixture on the tissue sections. After TUNEL labeling was completed, muscle sections were incubated with an anti-laminin monoclonal antibody (2E8; Hybridoma Bank, Univ. of Iowa) followed by an anti-mouse (Cy3 conjugate, C2181) and mounted with 4',6-diamidino-2-phenylindole (DAPI; Vectashield mounting medium). TUNEL- and DAPI-positive nuclei and laminin staining were examined under a fluorescence microscope, and the captured images were stacked using a SPOT RT camera (Diagnostic Instruments, Sterling Heights, MI) and SPOT RT software (Universal Imaging, Downingtown, PA). The number of TUNEL- and DAPI-positive nuclei was counted from six random, nonoverlapping fields at an objective magnification of x40. Only the labeled nuclei that were under the laminin staining were counted, to exclude any nonmuscle nuclei in the sections. Data were expressed as number of TUNEL-positive nuclei per 100 nuclei counted.
Statistical analyses. Statistical analyses were performed with the SYSTAT 11.0 software package. The effect of loading on muscle wet weight was determined by comparing muscle wet weights from control and loaded limbs with a paired t-test. The percent change in muscle wet weight was calculated for each individual animal, and the means from these data for each animal group (n = 6/group) are presented in Fig. 1. Satellite cell proliferation index, body weight, control or loaded soleus muscle weight, control or loaded plantaris muscle weight, Pax7-positive nuclei, BrdU-positive nuclei, protein expression levels, and nuclei number per muscle fiber were analyzed by two-way ANOVA (phenotype x treatment; control or loaded).The satellite cell proliferation index and protein expression were not compared between the 7 days postsurgery and 21 days postsurgery groups. Statistical significance was accepted at P < 0.05. All data are means ± SE.
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RESULTS |
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30% and 20% decreases in the number of myonuclei per muscle fiber cross section in plantaris and soleus muscles, respectively, of OZR vs. that shown in the LZR (Fig. 2E). Together, these data signify that, although the percentage of satellite cells (as indicated by Pax7) to total myonuclei is not reduced, there are less total myonuclei in the OZR. This suggests that there was not a preferential loss of satellite cells in the muscles of the OZR; rather, there was a proportional decrease in the number of satellite cells and myonuclei in muscles of OZR compared with that shown in LZR.
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DISCUSSION |
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Muscle hypertrophy in response to normal growth or muscle loading in adults is critically dependent on the proliferation and differentiation of satellite cells (30). Reduction in muscle DNA content (10) as a result of reduced muscle nuclei content (35) is one mechanism contributing to lower muscle transcriptional activity and muscle mass with aging and potentially leading to sarcopenia in aging. Thus it is possible that, in a similar fashion, reduced proliferation of satellite cells will contribute to lower nuclear content in skeletal muscle of OZR, which may have contributed to reduced muscle mass in control muscles compared with LZR. In this study, satellite cell proliferation was determined by identifying nuclei inside the basal lamina that had incorporated BrdU during compensatory hypertrophy of the plantaris muscle of OZR and LZR. We would not expect to see a high number of satellite cells being activated in adult skeletal muscle in humans under normal basal conditions. However, unlike humans, rodents continue to grow throughout their life cycle so one would expect to see a small amount of satellite cell proliferation even in adult rodent muscles. This expectation was confirmed in our finding of BrdU-positive myonuclei in the LZR control soleus and plantaris muscles. The initial hypothesis proposed for this study was that satellite cell proliferation would be inhibited in the OZR model of metabolic syndrome, regardless of loading. This hypothesis was partially confirmed by the almost complete absence of BrdU-positive myonuclei in the control plantaris and soleus muscles of the OZR. On the other hand, after loading, the number of BrdU-positive myonuclei was elevated in the LZR, but surprisingly there was an almost equal amount of BrdU-positive nuclei in the loaded plantaris muscle of the OZR and the LZR. We did anticipate that if satellite cell proliferation was restored it would coincide with a restoration of Akt and myogenic regulatory factor protein expression as we observed in this study. Previous studies from our laboratory and others have shown that loading-induced hypertrophy is accompanied by increases in MyoD and myogenin (2, 10), whereas muscle wasting and aging are usually accompanied by decreases or attenuated increases in protein levels of myogenic transcription factors (2, 15, 26). In old birds, the lower levels of myogenic regulatory factors appear to result from reduced contributions from satellite cells (25); however, restoration of myogenic regulatory factor levels from muscle loading could reflect changes in both myonuclei and satellite cells (25). In the present study, it is likely that the increased load on the plantaris muscle was sufficient to increase the activation of Akt in a contraction-dependent manner (32) and that the increase in Akt induced increased expression of myogenic regulatory factors (23).
Traditional treatments for metabolic syndrome, as recommended by the American Diabetes Association, include weight loss and aerobic exercise. Aerobic exercise increases whole body glucose disposal and improves insulin sensitivity, mainly through increased expression of GLUT4 protein (17). However, aerobic exercise is not considered an effective means to induce skeletal muscle hypertrophy. On the other hand, resistance exercise has also been shown to increase glucose transport into the muscle (38) and is widely accepted as a means to induce muscle hypertrophy.
To the best of our knowledge, this is the first study to demonstrate hypertrophy in an animal model of metabolic syndrome. It is important to note that metabolic syndrome did not limit muscle hypertrophic adaptations to increased loading. Another important finding of this study is that there was a restoration of Akt2 protein expression in hypertrophied muscles of OZR after overload. Akt2 specifically has been linked to disruptions in GLUT4 regulation, glucose uptake, and skeletal muscle hypertrophy (8, 11, 31). Skeletal muscle, by virtue of its mass, is the primary site for glucose and fatty acid oxidation, both of which are important complications with metabolic syndrome (6, 27). These findings suggest that resistance training, or some other form of loading, may be a viable addition to the treatment and/or prevention of metabolic syndrome in humans.
This is the first study in which satellite cell quantification and proliferation with metabolic syndrome has been investigated. We do not think that increased apoptotic signaling could account for the lower number of myonuclei and satellite cells in cross sections of control muscles of the OZR because we have failed to observe any increases in markers of apoptosis (TUNEL-positive nuclei; protein levels of AIF, Apaf-1, ARC, or BAD) in control muscles of the OZR compared with that shown in the LZR. Furthermore, it is unlikely that metabolic syndrome attenuates the sustained increases in ribosomes, thereby limiting translational capacity, as is the case in some chronic diseases (1), because, in the present study, the plantaris muscles had similar hypertrophic adaptations to compensatory loading in OZR and LZR. We speculate that lower Akt and MyoD levels in control muscles of OZR might in turn result in decreased satellite cell proliferation. This hypothesis is supported by recent data that show that leptin promotes proliferation and inhibits myogenin expression and myoblast differentiation in vitro (39); therefore, the lack of leptin might result in an inhibition of satellite cell proliferation. In the present study, there was a significant decrease in the protein expression of myogenic regulatory factors (myogenin and MyoD) and in Akt, which could account for the decreased satellite cell proliferation in the control muscles of the OZR. It is not clear whether the lower levels of MyoD and Akt are leptin dependent or independent or simply a response to or a consequence of metabolic syndrome. Thus it is possible that deficient leptin signaling or some other aspect of metabolic syndrome attenuates the expression of these proteins. To test this further, other models of obesity and metabolic syndrome would need to be investigated in which leptin levels were manipulated. Nevertheless, in the present study, MyoD, myogenin, and Akt protein expression were restored with loading, indicating that a significant stimulus such as compensatory loading is capable of overriding the attenuation of these proteins. Our results show that overload-induced muscle hypertrophy and satellite cell proliferation occur at similar levels in skeletal muscles of OZR and LZR, suggesting that satellite cell function per se is not limited in metabolic syndrome.
In conclusion, our data suggest that satellite cell proliferation is suppressed in control muscles of OZR with metabolic syndrome. This may lead to an impaired replacement of nuclei during normal turnover and, in turn, may contribute to the reduced number of myonuclei per muscle and the lower muscle mass in animals with metabolic syndrome. These findings underscore the need for further research to more fully understand the mechanisms responsible for attenuated satellite cell proliferation in control muscles in the OZR and to determine whether satellite cell activity or proliferation is reduced in other models of metabolic syndrome.
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ACKNOWLEDGMENTS |
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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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