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RECEPTORS AND SIGNAL TRANSDUCTION
B kinase and NF-B in contracting adult rat skeletal muscle
Research Division, Joslin Diabetes Center, and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
Submitted 22 December 2004 ; accepted in final form 7 May 2005
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ABSTRACT |
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 TOP ABSTRACT EXPERIMENTAL PROCEDURESRESULTSDISCUSSIONGRANTSREFERENCES |
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B (NF-B) is a transcription factor with important roles in regulating innate immune and inflammatory responses. NF-B is activated through the phosphorylation of its inhibitor, IB, by the IB kinase (IKK) complex. Physical exercise elicits changes in skeletal muscle gene expression, yet signaling cascades and transcription factors involved remain largely unknown. To determine whether NF-B signaling is regulated by exercise in vivo, rats were run on a motorized treadmill for 5–60 min. Exercise resulted in up to twofold increases in IKK
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phosphorylation in the soleus and red gastrocnemius muscles throughout the time course studied. In red gastrocnemius muscles, NF-B activity increased 50% 1–3 h after 60 min of treadmill exercise, returning to baseline by 5 h. Contraction of isolated extensor digitorum longus muscles in vitro increased IKK/ phosphorylation sevenfold and this was accompanied by a parallel increase in IB phosphorylation. Additional kinases that are activated by exercise include p38, extracellular-signal regulated protein kinase (ERK), and AMP-activated protein kinase (AMPK). Inhibitors of p38 (SB-203580) and ERK (U-0126) blunted contraction-mediated IKK phosphorylation by 39 ± 4% (P = 0.06) and 35 ± 10% (P = 0.09), respectively, and in combination by 76 ± 5% (P < 0.05), suggesting that these kinases might influence the activation of IKK and NF-B during exercise. In contrast, 5-aminoimidazole-4-carboxamide-1--D-ribofuranoside, an activator of AMPK, had no effect on either IKK or NF-B activity. In conclusion, acute submaximal exercise transiently stimulates NF-B signaling in skeletal muscle. This activation is a local event because it can occur in the absence of exercise-derived systemic factors. exercise; p38; ERK; AMPK signaling
Despite these advances in understanding the molecular regulation of contracting muscle fibers, it has become increasingly apparent that these signaling events do not explain all of the acute metabolic changes and long-term adaptations that occur in response to exercise. This fact, along with the complex nature of the contraction stimulus, suggests that contractile activity may stimulate additional signaling cascades in skeletal muscle. Nuclear factor-B (NF-B) has been studied most extensively for its central role in the regulation of innate immunity, inflammation, and apoptosis. In contrast, its physiological and pathological roles in cells outside of the immune system are only beginning to be understood. As a universal mechanism, NF-B dimers are sequestered basally in the cytoplasm by inhibitor of nuclear factor-B (IB). When activated, the IKK complex, consisting of two catalytic subunits (IKK and IKK) and a regulatory IKK
subunit, phosphorylates serine residues of IB and targets it for ubiquitination and proteosomal degradation (49). Liberation of the NF-B dimers (predominantly p50 and p65) promotes their nuclear translocation and NF-B-mediated gene transcription (34).
Several lines of evidence have led us to hypothesize that NF-B is regulated by exercise in skeletal muscle. Studies using cell systems or cardiac muscle have proposed that ERK, p38, and AMPK can regulate IKK/NF-B signaling (11, 33, 50). NF-B has also been shown to be regulated by elevations in intracellular calcium (23, 24) and reactive oxygen species (28, 35, 37, 46), both of which occur as a consequence of skeletal muscle contraction (4, 14, 31, 42). In fact, while this article was in preparation, Ji et al. (25) showed that exhaustive exercise resulted in increases in NF-B binding in rat skeletal muscle. In contrast to this finding, NF-B activity has also been reported to decrease in response to fatiguing skeletal muscle contraction (16). These data are intriguing due to recent findings, which have highlighted an important role for skeletal muscle NF-B in cachexia and other muscle wasting syndromes (7). Because sustained activation of NF-B leads to muscle wasting, we reasoned that discontinuous or episodic activation, as might occur during periods of exercise, could play an important role in normal muscle biology. In line with this hypothesis, acute exercise has been shown to induce apoptosis in skeletal muscle, an event involved in skeletal muscle plasticity, repair, and regeneration (40, 41, 44, 45).
In the present study we tested the hypothesis that submaximal exercise and contraction of isolated muscles activate IKK and NF-B. We demonstrate that both treadmill exercise in vivo and contraction in vitro activate IKK signaling in adult rat skeletal muscle and that this results in transient increases in NF-B activity postexercise. Data from inhibitor studies suggest that exercise-induced activation of IKK is influenced by both ERK and p38 MAPK.
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EXPERIMENTAL PROCEDURES |
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TOPABSTRACTEXPERIMENTAL PROCEDURESRESULTSDISCUSSIONGRANTSREFERENCES |
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/ (no. 2687), IKK (no. 2682), IKK (no. 2684), IB (no. 9242), phospho-p38 (CST no. 9211), phospho-ATF-2 (no. 9225), phospho-MAPKAPK2 (no. 3041), and phospho-AMPK1/2 (no. 2531) antibodies were purchased from Cell Signaling Technology (CST; Beverly, MA). Horseradish peroxidase-conjugated anti-mouse secondary antibodies were purchased from Amersham Biosciences (Piscataway, NJ), and anti-rabbit secondary antibody was from Zymed Laboratories (San Francisco, CA). U-0126 and SB-203580 were obtained from CST and Santa Cruz Biotechnology (Santa Cruz, CA), respectively. Animals and housing. All protocols for animal use were approved by the Institutional Animal Care and Use Committee of the Joslin Diabetes Center and were in accordance with National Institutes of Health guidelines. Male Sprague-Dawley rats (60–80 g for muscle incubation studies; 175–200 g for in vivo studies) were obtained from Taconic (Germantown, NY), provided standard rodent chow and water ad libitum, and were housed under standard laboratory conditions (12:12 h light-dark cycle). Animals were fasted 4 h before exercise and in vitro muscle contraction experiments described below.
In vivo treadmill exercise. Rats were familiarized with the treadmill (Quinton model 42) by running 5–10 min on the 2 days before the onset of experimentation. Animals were then subjected to a treadmill running protocol consisting of 5, 15, 30, or 60 min of moderate-intensity steady-state exercise (0.8 mph, 12% incline). Other animals were exercised for 60 min and euthanized 1, 3, or 5 h later. The rats were euthanized at the various times indicated in the figures by stunning and cervical dislocation. Soleus, red, and white gastrocnemius muscles were quickly separated, removed, and snap frozen in liquid nitrogen until subsequent processing and analyses.
Contraction of isolated muscles. Contraction experiments were performed as previously described (43). Briefly, fasted rats were euthanized by cervical dislocation and extensor digitorum longus (EDL) and soleus muscles were rapidly dissected. Both tendons were tied with a silk suture, mounted on an incubation apparatus to maintain resting length, and preincubated for 20 min in 37°C oxygenated Krebs-Ringer bicarbonate buffer (117 mM NaCl, 4.7 mM KCl, 2.5 mM CaCl2, 1.2 mM KH2PO4, 1.2 mM MgSO4, and 24.6 mM NaHCO3, pH 7.5) containing 2.0 mM pyruvic acid as an exogenous carbon source. Muscles were preincubated in U-0126 or SB-203580 for 20 min in concentrations indicated in the figures. After preincubation, muscles were transferred to a tissue support apparatus with stimulating electrodes (Harvard Apparatus, Holliston, MA) and incubated for an additional 10 min before the onset of contractions. Muscles were then stimulated for 10 min using the following protocol: train rate 2/min; train duration, 10 s; pulse rate, 100 Hz; pulse duration, 0.1 ms at 100 V. Force production was monitored during the entire contraction protocol with an isometric force transducer (Kent Scientific, Litchfield, CT) and a chart recorder (Kipp and Zonen, Delft, Holland). Immediately after contractions, muscles were removed from the buffer, dismounted, and snap-frozen in liquid nitrogen.
5-Aminomidazole-4-carboxamide-1--D-ribofurosanide treatment.
EDL muscles from fasted rats were isolated as described above. Muscles incubated in the presence or absence of 5-aminomidazole-4-carboxamide-1--D-ribofurosanide (AICAR; 2 mM) for 40 min were dismounted and snap-frozen in liquid nitrogen. For in vivo studies, fasted rats were treated with a maximal dose of AICAR (1.0 mg/g body wt) by intraperitoneal injection. A group of control rats were injected with saline. Sixty minutes after the injections, the rats were euthanized by stunning and cervical dislocation and mixed gastrocnemius muscles were quickly removed and snap-frozen in liquid nitrogen until subsequent processing and analyses.
Preparation of skeletal muscle lysates. Frozen muscles were pulverized and Polytron homogenized (Brinkman Instruments) in ice-cold lysis buffer (20 mM Tris, 5 mM EDTA, 10 mM Na3PO4, 100 mM NaF, 2 mM Na3VO4, 1% Nonidet P-40, 10 µM leupeptin, 3 mM benzamidine, 10 µg/ml aprotinin, and 1 mM phenylmethylsulfonyl fluoride, pH 7.5). Muscle homogenates were rotated end-over-end for 60 min at 4°C and centrifuged at 14,000 g for 10 min at 4°C. Protein concentrations of lysates were determined by the Bradford method with bovine serum albumin as a standard using a kit from Bio-Rad Laboratories (Hercules, CA). Muscle lysates were frozen in liquid nitrogen and stored at –80°C until used for immunoblotting.
Immunoblotting. Lysate proteins (40–100 µg) were separated by 8% SDS-PAGE, transferred to nitrocellulose membranes, and membranes were blocked for 60 min in Tris-buffered saline with 0.05–0.1% Tween 20 (TBST), and either 5% nonfat milk or bovine serum albumin. Proteins of interest were probed by incubating membranes in TBST containing 3–5% nonfat milk or bovine serum albumin and corresponding primary antibodies overnight on a rocker at 4°C. Membranes were then incubated with horseradish peroxidase-conjugated secondary antibodies (1:2,000) in TBST with 5% nonfat milk for 60 min at room temperature. Bands were visualized on film by enhanced chemiluminescence (Perkin-Elmer Life Sciences, Boston, MA), scanned, and quantitated by densitometry.
NF-B activity assays.
Gastrocnemius muscle protein was extracted through homogenization in passive lysis buffer (Promega, Madison, WI). Protein concentration was determined using the Bio-Rad Bradford protein assay. Electrophoretic mobility shift assays (EMSA) were performed using a Gel Shift Assay Systems Kit (Promega). Double-stranded consensus oligonucleotides (1.75 pmol/µl) for the NF-B binding site (5-AGTTGAGGGGACTTTCCCAGG-3) were labeled with T4 polynucleotide kinase (5–10 U/µl) and [-32P]ATP (3000Ci/mM) (Perkin-Elmer Life Sciences). End-labeled probe was purified through Sephadex G-25 spin column (Roche, Indianapolis, IN). Equal amounts of muscle protein (100 µg) were mixed with the labeled probe in the presence of 50 µg/ml poly(dI-dC) in 40 µl of binding buffer composed of 10 mM Tris·HCl, pH 7.5, 50 mM NaCl, 0.5 mM dithiothreitol, 1 mM MgCl2, and 10% glycerol. A 100-fold excess of cold probe was added into negative competitive control to ensure the specificity. After 30 min of incubation at room temperature, protein-DNA complexes were separated in a 3% polyacrylamide gel under nondenaturing conditions. Gels were subsequently dried, autoradiographied with a Storm phosphorimager (Molecular Dynamics), and analyzed using ImageQuant 5.1 software.
Statistical analyses. Data are expressed as means ± SE. Significance was determined a priori at P < 0.05. Student's t-test and ANOVA with Tukey's post hoc methods were used for group comparisons.
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RESULTS |
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TOPABSTRACTEXPERIMENTAL PROCEDURESRESULTSDISCUSSIONGRANTSREFERENCES |
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/ and NF-B are activated by exercise in vivo, rats performed moderate intensity, steady-state exercise on a treadmill for 5–60 min. Figure 1 shows that IKK/ phosphorylation in the red gastrocnemius was significantly increased above basal levels in response to the submaximal treadmill exercise bout. To determine the time course of IKK/ deactivation, additional rats were exercised for 60 min and studied 1 and 3 h later. This experiment showed that IKK/ phosphorylation returns to basal levels by 3 h postexercise. A single bout of exercise did not alter total amounts of IKK or IKK protein, consistent with our findings with other cellular kinases (6, 43). We did not observe exercise-induced alterations in IB protein levels (data not shown). Significant increases in IKK/ phosphorylation in response to 5, 15, and 30 min of exercise were observed in the soleus muscle (data not shown). Like the red gastrocnemius, exercise did not alter IKK, IKK, or IB protein levels in the soleus. The exercise protocol did not elicit significant changes in IKK/ phosphorylation in the white gastrocnemius muscle (data not shown).
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B DNA-binding activity increases in the period after exercise in vivo in rat skeletal muscle.
To determine whether exercise-mediated IKK phosphorylation translated into the activation of NF-B, muscle lysates were studied by EMSA. Maximal NF-B DNA binding activity was observed in red gastrocnemius muscle at 1 and 3 h after the cessation of 60 min of exercise and returned to baseline levels by 5 h (Fig. 1C).
Contraction of isolated skeletal muscle activates IKK.
IKK/ and NF-B are activated by circulating cytokines, such as TNF- and IL-1, as well as intracellular mediators such as reactive oxygen species. To determine whether exercise-mediated IKK/ phosphorylation is regulated systemically or locally, we incubated and contracted isolated rat EDL and soleus muscles. Figure 2A shows that IKK/ are phosphorylated by 10 min of contraction in EDL muscles, similar to treadmill exercise in vivo. Similar to exercise in vivo, total amounts of IKK, IKK, and IB protein were unchanged by contraction. The increase in IKK/ phosphorylation was accompanied by a significant increase in the phosphorylation of IB (Fig. 2B).
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B are often activated by proinflammatory stimuli, our isolated muscle experiments suggest that systemic factors may not be involved in exercise-induced IKK phosphorylation. Thus other kinases activated by exercise might play a role in the activation of IKK and NF-B. In particular, ERK and p38 are both regulated by muscle contraction and have been shown to regulate IKK activation in cell systems (11, 15, 33, 50). To test the hypothesis that ERK and p38 signaling are involved in the regulation of IKK phosphorylation, we used inhibitors of MEK (U-0126) or p38 (SB-203580) and measured contraction-induced IKK/ phosphorylation. For these experiments, we used both EDL and soleus muscles. Compared with vehicle, pretreatment of EDL muscles with U-0126 alone or SB-203580 alone tended to produce decreases in contraction-induced IKK/ phosphorylation, although these changes did not reach statistical significance (Fig. 3A). Pretreatment of soleus muscles with U-0126 or SB-203580 also did not result in significant decreases in contraction-induced IKK/ phosphorylation (Fig. 3B). We next determined whether ERK and p38 regulated IKK/ through distinct or redundant pathways. When EDL and soleus muscles were pretreated with a combination of U-0126 and SB-203580, the inhibition of contraction-induced IKK/ phosphorylation was additive (Fig. 3, A and B).
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AICAR does not alter IKK phosphorylation or NF-B activity.
AMPK is another kinase that is activated in muscle in response to exercise and has been shown to mediate oxidative stress-induced NF-B signaling in neuroblastoma cells (27). We determined whether AMPK activation by AICAR results in IKK phosphorylation in skeletal muscle. Rats were injected intraperitoneally with a maximal dose of AICAR and muscles were examined 60 min later. As shown in Fig. 4, compared with saline-injected controls, AMPK phosphorylation in skeletal muscle was significantly increased in response to AICAR treatment in vivo. Despite robust increases in AMPK phosphorylation, skeletal muscle IKK/ phosphorylation (Fig. 4, left) and NF-B activity (data not shown) did not change after 60 min of AICAR treatment. Shorter exposures to AICAR for 15 or 30 min also had no effect on IKK phosphorylation (data not shown).
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/ phosphorylation (Fig. 4). AICAR treatment in vivo or with incubated muscles also did not result in ERK or p38 phosphorylation, consistent with our inhibitor data showing that ERK and p38 are upstream regulators of IKK/ phosphorylation in contracting skeletal muscle. |
DISCUSSION |
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TOPABSTRACTEXPERIMENTAL PROCEDURESRESULTSDISCUSSIONGRANTSREFERENCES |
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/ increases in rat skeletal muscle during moderate intensity, steady-state exercise. Activation of these kinases in other tissues is tightly coupled to the stimulation of NF-B transcriptional activity. Consistent with this, we found that NF-B activity increased in muscle after exercise. We also show that IKK/ phosphorylation is regulated by contraction of isolated red (soleus) and white (EDL) muscles in vitro, in an ERK- and p38-dependent manner. The finding that IKK/ is regulated by contraction of isolated muscles provides insight into the mechanisms regulating this pathway. NF-B signaling has been shown to be regulated by elevations in intracellular calcium (23, 24) and reactive oxygen species (28, 35, 37, 46), both of which occur as a consequence of skeletal muscle contraction (4, 14, 31, 42). Furthermore, skeletal muscle-derived cytokines may activate IKK/ in an autocrine or paracrine manner. With the use of both in vivo and in vitro systems, our data demonstrate significant increases in IKK/ activation in response to exercise and muscle contraction. The activation of IKK/ is tightly coupled to NF-B activity, therefore, our data do not agree with the work by Durham et al. (16) who showed significant decreases in NF-B activity immediately following a similar contraction protocol. The differences in Durham's findings compared with our work may be partially explained by the muscles examined because strips of diaphragm were used in the previous study, whereas we examined whole EDL and soleus muscles.
In cells of the immune system, NF-B orchestrates the expression of over 150 target genes, including those encoding cytokines and chemokines, cytokine, chemokine, and immune receptors, stress response genes, cell adhesion molecules, regulators of apoptosis, and acute phase proteins (39). These proteins play pivotal roles in regulating innate immunity, inflammation, and apoptosis. The biology of NF-B in tissues outside of the immune system is less well understood. In muscle, we now know that even high-level activation of NF-B does not increase the expression of genes typically thought of as regulating immunity, inflammation, and apoptosis (7). Instead, sustained activation of NF-B in muscle leads to increased expression of MuRF1, a muscle-specific E3 ligase (5, 17), and the C2 and C9 subunits of the proteasome. The net effect of chronic, unopposed activation of NF-B in muscle is profound muscle wasting, much like that seen in cachexia, and muscle wasting syndromes associated with cancer, AIDS, bacterial sepsis, and immobilization (7). The opposite turns out to be true as well, that either genetic or pharmacological inhibition of NF-B prevents or reduces muscle wasting, for example in cancer and denervation, confirming that NF-B acts as a pathological mediator.
These findings raise intriguing questions about what effect episodic activation of NF-B, as occurs during intermittent exercise, might have on muscle physiology. Whereas sustained activation of this pathway causes muscle wasting, episodic activation might activate the same processes but with distinct end results. In fact, acute exercise has been shown to induce apoptosis in skeletal muscle (40, 41, 44, 45). Consistent with the possible involvement of NF-B in muscle damage, a previous report (25) showed prolonged increases in NF-B binding activity in deep vastus lateralis muscles after exhaustive exercise. Interestingly, our data demonstrate relatively rapid increases in IKK activation and transient postexercise increases in NF-B activity in red gastrocnemius muscles in response to a nonexhaustive, submaximal exercise protocol. Differences in the relative intensity of the exercise protocols likely explain the transient vs. prolonged increases in NF-B activation. The exhaustive nature of the exercise bout used in the previous study also might explain why they observed decreases in IB protein levels, whereas basal levels of IB were not altered by the moderate intensity exercise protocol used in the current study. Collectively, exercise-mediated NF-B activation is likely to play multiple roles, mediating cellular events in response to low- and moderate-intensity exercise, and regulating normal repair and regeneration after high-intensity exercise-induced muscle damage.
Physical exercise has been shown previously to induce the expression of a variety of potential NF-B target genes in skeletal muscle, including IL-1 (8, 36), IL-6 (26, 38), IL-8 (9, 36), IL-10 (36), TNF- (36), and MnSOD (22). In particular, skeletal muscle IL-6 production increases >100-fold during intense exercise (29, 47). Because persistent NF-B activation alone is not sufficient to induce the expression of these genes in skeletal muscle (7), it appears that exercise-mediated increases in these putative NF-B targets (e.g., IL-6) require additional signaling inputs. In cultured cells, IL-6 expression has also been shown to be p38 dependent (3, 12, 13, 30, 32, 50). Furthermore, p38-mediated IL-6 expression in cardiac myocytes is dependent on NF-B because a point mutation that abolishes the B site in the IL-6 promoter also abrogates p38-inducible IL-6 reporter activity (12). Our present findings implicate p38, as well as ERK, as kinases that influence the activities of IKK and NF-B in contracting skeletal muscle. This possibility is underscored by the fact that like NF-B, p38 is involved in the expression of numerous cytokines (33), and the degree of p38 activation is highly correlated with exercise-mediated skeletal muscle IL-6 expression (10). However, our data do not distinguish two possible mechanisms, one with p38 and ERK in linear pathways leading to IKK and NF-B activation and the second with p38 and ERK in parallel pathways. It is possible, in the second case, that cells respond to decreased p38 or ERK activity by dampening IKK/NF-B activity, and vice versa. Additional experiments will be needed to distinguish these possibilities.
In summary, we show that exercise in vivo and muscle contractile activity in vitro regulate NF-B signaling in adult skeletal muscle. Our data show that the IKK activation in response to exercise in vivo is a local event, triggered by either paracrine molecules and/or signals intrinsic to the muscle. We also provide evidence that p38 and ERK are likely involved in the coordinated activation of contraction-induced IKK activity. Furthermore, whereas AMPK has been implicated in the activation of NF-B, our data suggest that AMPK is not upstream in skeletal muscle IKK or NF-B activation. IKK and NF-B are novel exercise-induced signals in skeletal muscle that represent candidate regulators of gene expression during and following exercise.
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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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P < 0.05 vs. basal control.