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Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892
Address all correspondence and requests for reprints to: Peter Klover, 8 Center Drive, Building 8, Room 107, Bethesda, Maryland 20892-0822. E-mail: kloverp{at}mail.nih.gov.
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Introduction |
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STAT5b is more abundant in the skeletal muscle compared with other tissues, including liver and mammary gland (4). Little is known, however, about the importance of GH-STAT5 signaling in the skeletal muscle. It has been reported in C2C12 myoblasts, as well as in mouse and rat skeletal muscle, that GH treatment can induce IGF-I gene expression (5, 6, 7). IGF-I is a hormone of approximately 7 kDa and is essential for many actions of GH. The profound role of IGFs in growth was demonstrated by Igf1-, Igf2-, and Igfr-deficient animals, which are smaller than wild-type animals at birth and have severely retarded postnatal growth (8, 9). Impairments in IGF-I function have been linked to growth disorders, cancer, metabolic disorders such as type 2 diabetes, central nervous system disorders, and aging (10, 11, 12). Most circulating IGF-I is present in a ternary complex with IGF-binding protein 3 and the acid-labile subunit, which are important for increasing the half-life of the IGF-I peptide (13). IGF-I is produced by many tissues, but the liver is considered the primary source, responsible for about 75% of the circulating levels (14). Still, other tissues in the periphery likely account for a smaller percentage of circulating levels as well as local production. Despite the dominant role of the liver in producing circulating IGF-I, liver IGF-I-deficient (LID) mice do not have severe growth impairments and indicate that peripheral tissues are likely important for IGF-I production (14). However, mice with a total deficiency of acid-labile subunit crossed with the LID mice did show growth impairments, indicating a role for circulating IGF-I (15). In addition to its roles in growth, IGF-I has effects on glucose metabolism as well. The metabolic effects of IGF-I have been characterized as insulin-like, and this is likely because of the similar receptor pathways insulin and IGF-I share (8, 16). IGF-I can bind weakly to the insulin receptor, but strong glucose-lowering effects from IGF-I treatments have been observed in mice lacking the insulin receptor (17). Liver-derived IGF-I appears to have an important role in glucose metabolism through regulation of GH levels. LID mice develop peripheral insulin resistance, an effect attributed to increased GH levels (18).
The current study addressed the function of skeletal muscle STAT5-mediated cytokine signaling. Because of the requirement for STAT5 in GH actions, such as IGF-I production, conditional loss of STAT5 in the skeletal muscle provides a model to test the importance of a peripheral site of GH action. Here we report the impact of STAT5 deficiency in skeletal muscle on processes regulated by GH actions including postnatal body growth and glucose metabolism using a conditional gene knockout approach.
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Materials and Methods |
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GH injection and immunohistochemistry (IHC)
Recombinant mouse GH was provided by the National Hormone and Peptide Program and A. F. Parlow at Harbor-UCLA Medical Center (Torrance, CA). To visualize STAT5 in the nuclei by IHC, GH was injected at 2 µg/g body weight ip. After 30 min, quadriceps and liver were extracted and placed in 10% buffer-neutralized formalin at 4 C overnight and then placed in 70% ethanol. Tissues were paraffin embedded and sectioned. Quadriceps tissues were both cross and longitudinally sectioned. For histology, sections were deparaffinized in xylene and rehydrated in a series of ethanol dilutions. Antigen retrieval was done using a Digital Decloaking Chamber (Biocare Medical, Walnut Creek, CA). For immunostaining slides were blocked in 3% goat serum diluted in PBS with 0.05% Tween 20. STAT5b antibody (Santa Cruz Biotechnology, Santa Cruz, CA) was diluted 1:100 in PBS with 0.05% Tween 20 plus 3% goat serum. Fluorescence-conjugated secondary antibodies diluted 1:400 were applied to sections for 60 min in the dark at room temperature, washed in PBS, and mounted with VectaShield with 4',6-diamidino-2-phenylindole (Vector Laboratories, Burlingame, CA).
Western blot analysis
Proteins were extracted from muscle and liver tissues by rotor homogenization in 12 vol lysis buffer containing 50 mM HEPES (pH 7.4), 150 mM NaCl, 10% glycerol, 1% Triton X-100, 2 mM EDTA, 2 mM EGTA, 100 mM NaF, and protease inhibitor cocktail (Sigma Chemical Co., St. Louis, MO). Lysates were cleared by centrifugation at 4 C in a microfuge at maximum speed. Protein concentration was determined by Bradford reagent (Bio-Rad, Hercules, CA) using a final lysate dilution of 1:2000. Proteins were electrophoretically separated and transferred to nitrocellulose using the NuPAGE system (Invitrogen, Carlsbad, CA). Membranes were probed with STAT5a and STAT5b antibodies from Santa Cruz Biotechnology or actin antibody (Chemicon, Temecula, CA) as a loading control. Horseradish-peroxidase-conjugated secondary antibody (GE Healthcare, Piscataway, NJ) was then added. Finally, proteins were detected using enhanced chemiluminescence substrate (Pierce, Rockford, IL) and Kodak MR film (Kodak, Rochester, NY).
RNA extraction and real-time PCR
RNA from muscle and liver was extracted using the RNeasy RNA extraction kit (QIAGEN, Valencia, CA). Relative expression of IGF-I and STAT5a and STAT5b were measured using TaqMan probes (Applied Biosystems, Foster City, CA) for real-time PCR. Real-time PCR was carried out according to the manufacturer’s instructions using an ABI Prism 7900HT (Applied Biosystems). Individual PCRs were performed in triplicate on samples using mouse ß-actin as a housekeeping gene and experimental probes to obtain average cycle threshold (CT) values for these genes. Average ß-actin CT values were subtracted from experimental CT values to obtain 
CT values. CT values were then obtained by subtracting experimental sample CT values from the control sample CT. Relative gene expression was then calculated using 2–CT.
Serum hormone, free fatty acids (FFA), and triglycerides
Glucose, insulin, IGF-I, FFA, and triglycerides were assayed in the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Mouse Metabolism Core Laboratory (MMCL). For glucose, insulin, IGF-I, and GH, blood samples were taken in the fed state by retroorbital bleeds of 8- to 10-wk-old mice. Insulin levels were measured using a rat insulin RIA. Total IGF-I levels were measured from serum using RIA. GH levels were measured at the National Hormone and Peptide Program (Harbor-UCLA Medical Center).
Body composition
Lean body weight and fat mass was determined in the MMCL on live animals using an EchoMRI 3-in-1 QNMR system (Echo Medical Systems LLC, Houston, TX).
X-ray analysis
X-rays were taken on live, anesthetized mice in a Kodak Image Station In-Vivo FX system. Skeletal analysis was done on Kodak Molecular Imaging Software version 4.0.3.
Statistical analysis
Statistical differences in results were detected by using two-sample Student’s t test or single-factor ANOVA when more than two means were compared. Data are expressed as mean ± SEM. Differences in means were considered statistically significant when P < 0.05.
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Results |
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, top) and adult 8-wk-old mice (Fig. 1A, lower panels), as well as real-time PCR (Fig. 1B) demonstrated that STAT5 levels were reduced by approximately 80% in the quadriceps of Stat5MKO mice compared with controls. Acute injection of GH followed by necropsy after 30 min was used to identify activated STAT5b in nuclei of skeletal myocytes. Although strong staining was observed in control mice, STAT5b was not detected in myocyte nuclei of Stat5MKO by IHC (Fig. 1C). The muscle specificity of STAT5 deletion in Stat5MKO mice was confirmed by testing the loss of STAT5b expression in the liver. Western blot (Fig. 2A) and real-time PCR analysis (Fig. 2B) confirmed that STAT5 expression was not altered in the livers of Stat5MKO mice. Nuclear STAT5b was equally apparent in hepatocytes of control and Stat5MKO mice by IHC (Fig. 2C). These results demonstrate that Stat5MKO mice have lost STAT5 protein expression selectively in skeletal muscle and therefore are a suitable model to test the role of STAT5-dependent cytokine action in skeletal muscle.
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). Even more striking was the reduced growth of male Stat5MKO mice. Significant differences in body weights were evident after 4 wk, and by 8 wk, Stat5MKO males were almost 20% smaller than controls (Fig. 3B). The distinct effects of STAT5 deletion on growth patterns between Stat5MKO males are consistent with the known sexually dimorphic pattern of GH pulses in rodents. Additionally, it has been demonstrated that complete loss of STAT5b has a more pronounced effect on male body growth than females (3). To study skeletal growth, x-rays were taken of anesthetized 8- to 10-wk-old male and female mice (Fig. 4A). Software analysis of x-rays demonstrated that the smaller Stat5MKO mice had shorter skeletons from nose to anus (Fig. 4B). Collectively. results from x-ray analysis indicate male and female Stat5MKO mice have smaller skeletons than controls.
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dashed lines) and male (Fig. 5b, dashed lines) Stat5M/LKO mice measured from 3 to 12 wk of age were nearly identical to Stat5MKO mice, with male Stat5M/LKO mice body weight reaching approximately 20% less than controls at 8 wk. Therefore, the combined deletion of STAT5 in muscle and liver did not further reduce the size of these animals.
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). Corrected for body weight, however, there was no difference in fraction of lean or fraction of fat mass (Fig. 6B). In contrast, adult mice displayed differences in body composition. In addition to reduced body weight (Fig. 6C), Stat5MKO males had significantly reduced lean mass (Fig. 6D). Lean mass as a fraction of total body weight was relatively unchanged in Stat5MKO mice (Fig. 6E), indicating the loss of body weight was mostly accounted for by loss of lean mass. This was despite a trend toward higher total fat mass (Fig. 6F) in Stat5MKO mice. Therefore, the smaller size of Stat5MKO mice was due to a decrease in lean mass and was not the result of a reduced fat mass. The body composition of Stat5M/LKO mice was similar to Stat5MKO mice, displaying a reduction in fraction of lean mass (Fig. 6E) and a modest increase in body fat (Fig. 6F). These results indicate that the presence of skeletal muscle STAT5, but not hepatic STAT5, impacts postnatal growth of lean tissues. Together, these results suggest that GH signaling through STAT5 in the skeletal muscle is more important than in liver for postnatal body growth.
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). In the liver, no change in IGF-I mRNA levels was seen (Fig. 7B), which further confirms results that STAT5 deletion does not occur in this tissue. These results demonstrate reduced IGF-I expression in skeletal muscle and strongly suggest that GH-dependent IGF-I production from the skeletal muscle is largely mediated by STAT5.
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). A large reduction would not be expected in these animals because roughly 75% of circulating IGF-I is hepatic derived. In contrast, the Stat5M/LKO mice had an almost 60% reduction in serum IGF-I (Fig. 7C). At 4 wk of age, when the Stat5MKO mice are roughly the same size as controls, there was no difference detected in serum IGF-I (n = 4) (Fig. 6D). Reduced serum IGF-I has been associated with a compensatory increase in GH levels (12). Compared with controls, neither male nor female Stat5MKO mice showed elevation in GH levels (male controls 21.36 ± 4.79 ng/ml, n = 11; male Stat5MKO 14.25 ± 5.88 ng/ml, n = 4; P > 0.05). Together, these results suggest that skeletal muscle contributes at most only a small portion toward circulating IGF-I levels, and this amount did not result in a change of GH levels.
Hepatic-derived IGF-I contributes to insulin sensitivity in mice (12). It is uncertain to what extent STAT5-dependent skeletal muscle IGF-I influences whole-animal glucose homeostasis. To test whether glucose metabolism was altered in Stat5MKO mice, metabolic parameters were measured in the blood of adult freely fed animals. Serum glucose, insulin, and FFA were not different between Stat5MKO and controls (Table 1). However, serum triglycerides were significantly elevated in Stat5MKO mice. To determine whether tolerance to glucose challenge was altered in Stat5MKO mice, glucose tolerance tests (GTT) were performed by ip injection of 2 g/kg glucose into overnight-fasted adult mice. At time zero, fasting glucose was not different between Stat5MKO and controls in both male and female mice. In contrast, after glucose challenge, significant glucose intolerance was observed in male Stat5MKO mice, with the 30- and 60-min time points being the most affected (Fig. 8B). In females, a similar trend was seen, although the defect was less severe and did not reach statistical significance (P > 0.05) (Fig. 8A). To measure whole-animal insulin sensitivity toward exogenous insulin, insulin tolerance tests (ITT) were used. Neither females (Fig. 8C) nor males (Fig. 8D) showed markedly changed insulin sensitivity as assessed by glucose disposal. Together, these results indicate that reduced STAT5 signaling in the skeletal muscle can lead to glucose intolerance, especially in male mice, although insulin sensitivity may not be markedly altered.
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Discussion |
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It has previously been observed that growth defects in STAT5b-deficient male mice were more pronounced than in females (2, 3). In contrast, Teglund and colleagues (2) reported that both 12-wk-old male (30–40% growth reduction) and female (20–30% growth reduction) STAT5a/bN mice had growth defects, suggesting a role for STAT5a as well. Although the growth reduction was less severe in Stat5MKO mice (
20% in males vs. 12% in females from 8–10 wk), our results were consistent with this finding, because loss of both STAT5a and STAT5b in muscle produced growth reduction in both male and female mice. We therefore conclude that STAT5a/b transcription factors in the skeletal muscle are essential for normal postnatal growth, with additional contributions from other tissues.
Stat5b activates transcription of the IGF-I gene in liver, but the importance of this signaling pathway in the skeletal muscle was unknown. Our results suggest that one mechanism by which skeletal muscle STAT5 controls body growth is through local autocrine and/or paracrine actions of IGF-I. Deletion of skeletal muscle STAT5 in Stat5MKO mice led to a 60% reduction in IGF-I mRNA in this tissue and a modest decline in circulating IGF-I. Although there is no evidence that a small decrease in circulating IGF-I contributed to the growth retardation of Stat5MKO mice, it indicates that the skeletal muscle is capable of IGF-I production and secretion. In addition, IGF-I is known to have insulin-sensitizing effects, and IGF-I deficiency is known to result in insulin resistance. Stat5MKO mice did not have obvious insulin resistance by ITT but did show reduced glucose tolerance, which may point to a reduction in available IGF-I as a result of skeletal muscle STAT5 deficiency. This apparent discrepancy may be reconciled by either a change in islet function in Stat5MKO mice, or alternatively, production of endogenous insulin during the GTT was enough to reveal insulin resistance in the Stat5MKO, whereas the large bolus of insulin in the ITT overcame the insulin resistance. Taken together, these results suggest that STAT5-dependent actions in the skeletal muscle lead to production of localized IGF-I that is essential for normal postnatal growth.
In animals with liver-specific IGF-I deficiency (14), circulating IGF-I is not completely removed; therefore, it is possible that the remaining circulating levels are sufficient for normal growth. An alternative explanation can be proposed in which GH-stimulated IGF-I produced in peripheral tissues (especially in the presence of elevated GH) acts in an autocrine and/or paracrine manner to drive postnatal growth. It is very likely a balance of some combination of peripheral and endocrine IGF-I controls postnatal growth and that both endocrine and autocrine and/or paracrine mechanisms of IGF-I action have important roles in promoting growth. A disruption of this balance, such as seen in the LID mouse (14) may lead to compensation by peripheral tissues, including the skeletal muscle. Here we support this possibility by demonstrating that GH action in the skeletal muscle is important for postnatal growth despite the fact that the skeletal muscle is only a minor source of circulating IGF-I. We also hypothesized that if skeletal muscle compensates for loss of hepatic IGF-I production, then disrupting both liver and muscle STAT5 would lead to additive effects on growth. To our surprise, in Stat5L/MKO mice (loss of both liver and skeletal muscle STAT5), postnatal growth was nearly identical to that of Stat5MKO mice. Therefore, our data suggest that local IGF-I production is more important for postnatal growth than circulating, hepatic-produced IGF-I.
IGF-I is also produced by other tissues including bone, and these tissues likely play important roles in IGF-I-dependent postnatal growth. IGFs are known to be essential for normal bone growth and formation (25, 26). Skeletal IGF-I signaling has an important role in this process because conditional deletion studies show that IGF-I receptors in osteoblasts are essential for bone matrix mineralization (26). Additionally, it is known that GH and IGF-I can act directly to stimulate the growth plates of bone, indicating endocrine IGF-I is not necessary to mediate a response of GH (27, 28). Because skeletal muscles are in contact with bones, cross-talk between these two tissues would be natural. Results from the current study suggest that skeletal muscle-produced IGF-I is important as well for normal bone growth and may act in concert with normal skeletal-derived IGF-I. The skeletons of the Stat5MKO mice were clearly shorter than those of control littermates, demonstrating bone growth was stunted in these mice. Our results therefore suggest that STAT5-dependent IGF-I in the skeletal muscle contributes to reduced skeleton size.
Other GH-dependent factors besides IGF-I could play a role in skeletal muscle growth as well. It has recently been reported that GH causes growth of skeletal myotubes independently of IGF-I (29). There, the authors reported that GH caused an increase in myotube size but did not induce STAT5 phosphorylation or IGF-I expression. Additionally, GH and IGF-I had additive effects on cell size, indicating an IGF-I-independent mechanism of GH action. In the current study, we show robust STAT5 translocation to the nucleus of myocytes 30 min after GH injection of mice, indicating STAT5 formed a phosphorylated, transcriptionally active complex in response to GH (Fig. 1). In addition, the small but significant drop in circulating IGF-I levels in Stat5MKO mice we observed indicates that skeletal muscle produces IGF-I. Although it remains a likely possibility that IGF-I produced by skeletal muscle or other tissues does not control all aspects of GH-dependent skeletal muscle growth, one explanation for the apparent contradiction between our results and those in primary myotubes may be that there are differences between the way GH signals in isolated myotubes in vitro and GH signaling in vivo.
IGF-I mediates many GH responses, but there are IGF-I-independent roles of GH as well. This is evidenced by the well-known fact that IGF-I and GH treatments have very different metabolic consequences. IGF-I treatments promote insulin action, whereas GH treatments cause insulin resistance (16). In a study examining growth aspects of GH and IGF-I, additive effects on growth retardation of Ghr/Igf1 double-knockout animals were identified (9). These studies point to IGF-I-independent mechanisms of GH signaling. Therefore, although IGF-I remains the strongest candidate for mediating the STAT5-dependent GH action in skeletal muscle, other factors should not be ruled out.
The results of the current study demonstrate that the transcription factors STAT5a/b in the skeletal muscle are necessary for normal postnatal growth of mice. Additionally, our studies point to an important autocrine and/or paracrine role of Stat5-dependent IGF-I produced by skeletal muscle that is at least as important for growth as circulating, hepatic STAT5-dependent IGF-I. These studies provide new insight into the targets of GH and the peripheral sites of IGF-I production that are necessary for postnatal growth.
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Acknowledgments |
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Footnotes |
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Disclosure Statement: The authors have nothing to disclose.
First Published Online December 7, 2006
Abbreviations: CT, Cycle threshold; FFA, free fatty acids; GTT, glucose tolerance test; IHC, immunohistochemistry; ITT, insulin tolerance test; LID, liver-specific deletion of IGF-I; STAT, signal transducers and activators of transcription.
Received October 25, 2006.
Accepted for publication November 30, 2006.
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) and Stat5MKO (
) mice weighed at weekly intervals (n = 12–15); B, growth curves of male control (
- - -) mice weighed at weekly intervals (n = 12–15); B, growth curves of male control (
