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B in skeletal muscle nuclei
1Pulmonary and Critical Care Medicine Section, Baylor College of Medicine, Houston, Texas 77030; 2Department of Physiology, University of Kentucky, Lexington, Kentucky 40536; 3Metabolism, Shriners Burns Hospital, and Department of Surgery, University of Texas Medical Branch, Galveston, Texas 77555
Submitted 28 January 2004 ; accepted in final form 15 June 2004
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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B (NF-B), a putative regulator of muscle protein breakdown. Muscle biopsies were obtained from the vastus lateralis of healthy humans before, immediately after, and 1 h after fatiguing resistance exercise of the lower limbs. Biopsies were analyzed for nuclear NF-B DNA binding activity by using electrophoretic mobility shift assay. NF-B activity, measured immediately after exercise, was less than preexercise activity; after 1-h recovery, activity returned to preexercise levels. In follow-up studies in adult mice, basal NF-B activity varied among individual muscles. NF-B activity in diaphragm fiber bundles was decreased after a 10-min bout of fatiguing tetanic contractions in vitro. NF-B activity in soleus was increased by 12 days of unloading by hindlimb suspension; this increase was reversed by 10 min of fatiguing exercise. These data provide no support for our original hypothesis. Instead, acute fatiguing exercise appears to decrease NF-B activity in muscle under a variety of conditions. signal transduction; muscle contraction; transcription factor; oxidative stress
B (NF-B) is an inducible transcription factor that regulates the expression of numerous genes involved in immune and inflammatory responses, as well as cell growth and survival (9, 28). NF-B consists of two subunits drawn from the NF-B/Rel family, with the most abundant form being a heterodimer composed of the p65 (RelA) and p50 (NF-B1) subunits (9, 28). Under basal conditions, NF-B is sequestered in the cytosol by physical association with its inhibitor (I-B
), which covers the nuclear localization signal of NF-B. On stimulation by a variety of factors, I-B is dissociated from NF-B, exposing the nuclear localization signal and resulting in translocation of NF-B to the nucleus, where it modulates transcription by binding to DNA in the promoter region of target genes.
Recent findings suggest that NF-B plays a role in the regulation of skeletal muscle metabolism. Most prominently, NF-B has been implicated as a modulator of muscle catabolism. Prolonged unloading of antigravity limb muscles in mice leads to muscle atrophy (5, 19) and NF-B activation (8), an effect that may be linked to excessive reactive oxygen production (13). TNF-, a catabolic cytokine, also rapidly activates NF-B in skeletal muscle (7, 14, 15, 17). In addition, recent studies point to a possible role of the NF-B pathway in insulin resistance (12).
Given the potential importance of NF-B in skeletal muscle, it is surprising that the effects of muscle contraction on NF-B activity have not been determined. Contractile activity increases production of muscle-derived reactive oxygen species (ROS) (25). In turn, ROS increase NF-B activity in a variety of cell types (9) and are required for NF-B activation in TNF--stimulated myocytes (15). We, therefore, hypothesized that strenuous muscle contraction would increase NF-B activity in skeletal muscle and conducted experiments in healthy volunteers and in isolated murine muscles to test this hypothesis.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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Subject characteristics and preliminary testing.
Human studies were conducted in the exercise laboratory at the Shriner's Hospital for Children, an outpatient facility of the Clinical Research Center at the University of Texas Medical Branch in Galveston, TX. The study was approved by the Institutional Review Board of the University of Texas Medical Branch in Galveston. Five subjects (4 men, 1 woman) consented to participate after receiving a detailed written and verbal description of the study. The age, height, weight, body mass index, and leg volume [means ± SE (range)] were 27 ± 3 yr (21–34 yr), 1.77 ± 0.05 m (1.62–1.87 m), 86 ± 7 kg (66–105 kg), 27 ± 1 kg/m2 (25–30 kg/m2), and 11.5 ± 0.9 liters (9.4–14.5 liters), respectively. The one repetition maximum (1 RM) for the leg press and knee extension were determined for each subject on the day of the initial screening, typically 
1 wk before the study day. For both maneuvers, subject position was noted, and the same equipment settings (e.g., seat height, back support position, etc.) were used on the day of the study. For each maneuver, the subject performed a warm-up set of 
10 repetitions at a comfortable weight, followed by single repetitions at progressively greater weights until the subject was no longer able to complete the lift. The subject rested 1–2 min between each repetition. For knee extension, the 1 RM of each leg was tested and, if a difference between the legs was noted, the 1 RM of the weaker leg was used. Leg volume was estimated by using an anthropometric method (10).
Procedure.
Subjects reported to the General Clinical Research Center at the University of Texas Medical Branch in Galveston the evening before the study and were fasted from 10:00 PM until the completion of the study the next day. The next morning, the subjects were transported to the Exercise Laboratory of the Shriners Burns Institute, affiliated with the General Clinical Research Center of the University of Texas Medical Branch at Galveston, where they rested for at least 1 h. Following this hour, the subjects performed 45 min of lower body resistance exercise. This exercise consisted of approximately eight sets of 10 repetitions of leg press at 75% of the 1 RM followed by eight sets of eight repetitions of knee extension with each leg, separately, at 80% of 1 RM. Muscle biopsies from the vastus lateralis were collected at rest (n = 4), immediately postexercise (n = 3), and 1 h postexercise (n = 4). Biopsies were rinsed in ice-cold saline and dissected free of visible fat and connective tissue before freezing in liquid nitrogen.
Animal Studies
Muscle isolation.
The animal protocol was approved by the Animal Care Committee at Baylor College of Medicine. Male ICR mice were maintained on a 12:12-h light-dark cycle. Mice were anesthetized by isoflurane inhalation and killed by cervical dislocation before tissue removal. To compare basal NF-B activity in a variety of muscle and tissue types, samples of diaphragm, heart, liver, gastrocnemius, soleus, and extensor digitorum longus were removed, blotted dry, and quickly frozen in liquid nitrogen. To assess contractile function, diaphragm or soleus muscles were removed and prepared for study in vitro.
Contractile studies. For the diaphragm experiments, the muscle was quickly removed and placed in Krebs-Ringer solution (137 mM NaCl, 5 mM KCl, 1 mM NaH2PO4, 24 mM NaHCO3, 2 mM CaCl2, and 1 mM MgSO4) and gassed continuously with 95% O2 and 5% CO2, at room temperature. Fiber bundles were cut parallel to the fibers, taking care to leave the rib and central tendon attached at either end. The rib was tied to a tissue support rod (Radnoti Glass Technology, Monrovia, CA) by using 5-0 silk suture, and the muscle was positioned in a temperature-controlled tissue bath (Radnoti). The central tendon was similarly attached to a force transducer. The transducer was mounted on a micrometer, which allowed muscle length to be adjusted in 0.1-mm intervals. Muscle length was adjusted to maximize twitch force (optimal length). Muscle bundles were stimulated by field stimulation. In preliminary experiments, it was determined that 16 V produced supramaximal stimulation of fiber bundles; accordingly, this voltage was used for all experiments. For studies of soleus, the entire muscle was removed intact, tied to support rods, and then stimulated in the same manner as the diaphragm fiber bundles.
After determination of optimal length, the muscle bath was heated to 37°C. Diaphragm fiber bundles were subjected to one of three contractile protocols, whereas solei were subjected to only the second of the three protocols (see below). In the first protocol, twitch force and maximal tetanic force (Po; 300 Hz, 500-ms train duration) were determined by using a 2-min interval between measurements. Two minutes after the determination of Po, fiber bundles were stimulated for 1 min of submaximal tetanic contractions (40 Hz, 500 ms/train, 0.5 trains/s). Immediately following the stimulation protocol, fiber bundle length was measured by using electronic calipers, the rib and central tendon were dissected away, and excess buffer was blotted from the surface. The fiber bundle then was weighed and quickly frozen by using liquid nitrogen or dry ice. In the second protocol, maximal twitch force and Po were determined as in the first protocol, followed 2 min later by 10 min of submaximal tetanic contractions (40 Hz, 500 ms/train, 0.5 trains/s). Both diaphragm fiber bundles and solei were subjected to this protocol. Muscles were measured and collected as described above. In the third protocol, diaphragm fiber bundles were stimulated as in protocol 2 and were collected 1 h after the stimulation protocol was completed.
Hindlimb unloading protocol.
Based on the results from the in vitro contractile studies and a previous study that found muscle unloading activated NF-B (8), we were interested in the effects of contraction on unloading-induced NF-B activity. A protocol approved by the Baylor Animal Care Committee was used to unload the hindlimb antigravity muscles of adult mice. Animals were randomly assigned to normal cage activity or hindlimb unloading for 11–12 days. Unloaded mice were partially suspended by their tails; the animals were able to move about the cage using their forelegs, but their hindlimbs were not weight bearing. The unloaded mice had free access to water and food, as did the control mice, and continued to groom themselves while suspended. Body weight of the unloaded mice was stable during unloading, whereas the body weight of nonsuspended control mice increased over the same period. At the completion of the unloading period, mice were killed under anesthesia by cervical dislocation, and both solei were removed and frozen for later processing. In five animals, one of the unloaded solei was subjected to the contraction protocol described above (protocol 2) to determine the response of NF-B to contraction following muscle unloading.
Tissue Processing
Preparation of cell extracts.
Cytoplasmic extracts were prepared by grinding muscle samples in a solution containing 10 mM HEPES-KOH (pH 7.9), 1.5 mM MgCl2, 10 mM KCl, 2 µg/ml aprotinin, 1 µg/ml leupeptin, 1 mM dithiothreitol (DTT), and 2 mM phenylmethylsulfonyl fluoride. Samples were ground in a glass tissue grinder cooled in an ice water slurry. After grinding, samples were vortexed, incubated on ice for 10 min, vortexed again, and then frozen on dry ice. After thawing in cool water, samples were vortexed a final time and centrifuged for 10 s at 4°C at 16,110 g. The supernatant, containing the cytoplasmic extract, was then removed and not used for further analysis in this study. Nuclear extracts were prepared by resuspending the pellet in a buffer containing 20 mM HEPES-KOH (pH 7.9), 1.5 mM MgCl2, 5% glycerol, 420 mM NaCl, 0.2 mM EDTA, 2 µg/ml aprotinin, 1 µg/ml leupeptin, 1 mM DTT, and 2 mM phenylmethylsulfonyl fluoride and incubating for 30 min at 4°C. During incubation, samples were vortexed 10 s every 10 min. After incubation, the samples were centrifuged for 4 min at 4°C, and the supernatant, containing the nuclear proteins, was collected.
Protein determination. To determine cytosolic and nuclear protein concentrations, 999 µl of a 1:4 mixture of Bio-Rad concentrated dye reagent and water were added to 1 µl of extract. The sample was vortexed, and the absorbance at 595 nm was measured. Protein concentration was determined by using a standard curve of absorbance vs. concentration of bovine serum albumin. Samples and standards were analyzed in triplicate.
Electrophoretic mobility shift assay.
Binding reactions were performed by using 3- to 10-µg nuclear protein combined with 1 ng of NF-B binding DNA probe (5'-AGTTGAGGGGACTTTCCCAGGC-3'; consensus NF-B binding sequence underlined), labeled with [-32P]dATP (Amersham-Pharmacia) by using the Klenow fragment. Binding reactions were carried out in binding buffer containing 10 mM Tris·HCl (pH 7.5), 10% glycerol, 0.05% Nonidet P-40, 0.1 µg/µl bovine serum albumin, 0.05 µg/µl poly(dI-dC), and 500 µM DTT. Samples were incubated on ice for 30 min. Binding specificity was confirmed by using antibodies to the Rel B, p52, c-Rel, p50, and p65 subunits of NF-B (Santa Cruz Biotechnology, Santa Cruz, CA), which were added 15 min into the incubation. Lanes containing increasing amounts of protein were loaded to verify that measurements of NF-B activity were linear (see Fig. 2). After incubation, samples were resolved on 5% polyacrylamide gels. After drying, gels were exposed to X-ray film and analyzed by using commercial densitometry software (ImageQuant 5.2, Amersham Biosciences, Piscataway, NJ).
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Differences between treatments were compared by using two-tailed t-tests. When control and experimental samples were not from the same animal, densitometric values were normalized to the average value for all control lanes on a particular gel, and an unpaired t-test was performed. When control and experimental samples were from the same animal or person, each experimental sample was normalized to its own control, and a paired t-test was performed. A one-way analysis of variance with Tukey’s post hoc analysis (GraphPad Prism, www.graphpad.com) was used to test for differences among muscle types and liver. A P value <0.05 was considered significant.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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To determine the response of NF-B to muscle contraction in vivo, we studied human volunteers before, immediately after, and 1 h after a strenuous workout of lower body resistance exercise. The maximal performances of the subjects on the two lifts, determined at least 1 wk before the day of the study, are given in Table 1 and were similar to normal values for these two lifts reported previously (3). On the day of the study, subjects attempted to perform a workout consisting of eight sets of leg press at 75% of 1 RM and eight sets of knee extensions at 80% of 1 RM. The workout induced fatigue; even with encouragement and assistance ("spotting"), only one subject was able to complete the workout as designed. Subjects averaged 69 ± 2% of 1 RM for the leg press and 60 ± 6% of 1 RM for knee extension during the exercise bout.
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B activity was detectable in muscle biopsies obtained from all subjects before exercise (Fig. 1). Contrary to our hypothesis, NF-B activity was reduced immediately postexercise in every subject studied (Fig. 1A). This decrement spontaneously reversed with 1 h of postexercise bed rest, after which NF-B activity had returned to baseline (Fig. 1B).
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To determine whether NF-B activity varies according to muscle or tissue type, we measured basal NF-B activities in a panel of striated muscles and in liver (Fig. 2). NF-B activity was detectable in all samples studied. Heart, diaphragm, soleus, and liver exhibited similar activity levels; the values measured in gastrocnemius and extensor digitorum longus muscles were lower.
Fatiguing Exercise in Vitro
Resistance exercise induces systemic responses (e.g., hormonal, cardiovascular) that may influence the response of NF-B to muscle contraction. To study the direct effects of strenuous contraction on NF-B activity, we stimulated diaphragm fiber bundles from mice to contract in vitro. Ten minutes of contractions caused muscle fatigue, as evidenced by a 75 ± 5% reduction in muscle force production during the protocol (Fig. 3). As in human studies, basal NF-B activity was evident in unfatigued fiber bundles and was decreased by fatiguing contractions (Fig. 4), declining 44% from basal levels. Continued incubation under passive conditions did not reverse this effect; 1 h after the fatigue protocol, NF-B activity remained significantly less than control (data not shown). To test for time- and/or fatigue-dependent effects, we also evaluated fiber bundles conditioned by 1 min of repetitive contractions, a protocol designed to avoid overt fatigue (Fig. 3). As shown in Fig. 5, the 1-min protocol caused a modest reduction in NF-B activity that was not statistically significant. Supershift analyses showed that muscle contraction did not alter the NF-B subunit composition.
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Having discovered that muscle contraction reduced NF-B activity, we were curious whether muscle contraction would reduce the elevated NF-B activity characteristic of unloaded muscle. Hindlimb unloading for 11–12 days caused soleus weight to decrease by 53% relative to the muscles of freely ambulating controls (3.4 ± 0.01 mg unloaded vs. 7.3 ± 0.3 mg control; P < 0.001) and caused nuclear NF-B activity to increase without affecting the NF-B subunit composition (Fig. 6A). This chronic elevation was acutely reversed by a 10-min bout of strenuous contractions in vitro; after exercise, the NF-B activity in unloaded muscles was not significantly different from control. As in diaphragm fiber bundles, the contraction protocol induced fatigue of soleus muscles, decreasing force by 85% over 10 min (Fig. 6B). However, this protocol did not alter NF-B activity in soleus obtained from freely ambulating mice (data not shown).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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B. We were wrong. The present study shows that fatiguing muscle contractions rapidly diminish NF-B activity in both human and mouse skeletal muscle nuclei and oppose the increase in NF-B activity caused by prolonged muscle unloading.
Our data provide information about the regulation of this response. First, in vitro experiments demonstrate that hemodynamic and hormonal inputs are not required for the drop in NF-B activity caused by exercise. The present data do not rule out a neural signaling mechanism, however, because peripheral motor and autonomic nerve endings retain excitability in excised muscle preparations and are depolarized by supramaximal field stimulation. Second, the degree of NF-B inhibition appears to vary with exercise duration. Activity was decreased after 10 min but not after 1 min of repetitive contractions. Third, the response is transient. One hour of bed rest after exercise was sufficient for complete recovery of NF-B activity in the muscles of healthy subjects. Such recovery did not occur in murine muscles that underwent 1-h passive incubation in vitro. Perhaps a systemic stimulus is required for recovery of NF-B activity, or NF-B signaling may be restored more slowly in mouse than human muscle. It is also possible that biopsy sampling of human muscle causes activation of NF-B, which is counteracted during exercise but becomes evident during recovery.
Our observation that DNA binding activity of NF-B is increased in the nuclei of unloaded soleus is consistent with the observations of Hunter and coworkers (8). They found that hindlimb suspension stimulates expression of a NF-B-driven reporter gene and increases nuclear levels of the p50 subunit of NF-B in unloaded soleus. The data from these two studies suggest that NF-B signaling might contribute to the loss of muscle mass induced by unloading. The increased NF-B activity observed during unloading may be secondary to unloading-induced increases in ROS (13). Similarly, NF-B appears to play an essential role in muscle wasting stimulated by TNF-. In cultured muscle cells, NF-B activation is required for the increase in ubiquitin conjugating activity (16), loss of muscle protein (17), and changes in myogenesis (7, 14, 18) induced by TNF- exposure. To the extent that NF-B drives muscle catabolism, it is reasonable that strenuous exercise would inhibit NF-B signaling and thereby protect muscle mass.
Exercise-induced inhibition of NF-B might also influence insulin sensitivity. In adipocytes, NF-B mediates the insulin resistance induced by TNF- (26). In skeletal muscle, dietary fat-induced insulin resistance is regulated by I-B kinase, which targets I-B for degradation and activates NF-B (12). Also, NF-B appears to promote lipid accumulation (4), which is linked to insulin resistance (11). These data predict that NF-B inhibition will stimulate insulin sensitivity and increase glucose uptake by muscle, classic responses to strenuous exercise (27).
NF-B activity was detected in human vastus lateralis and in murine tissues before exercise. This finding suggests that NF-B continually modulates gene expression, but the physiological significance of this signal is not clear. NF-B opposes apoptosis in many postmitotic cell types (9). Perhaps tonic activity contributes to the resistance of skeletal muscle fibers to apoptosis, or basal NF-B activity might be linked to aerobic adaptation. Activity was greatest in heart, diaphragm, soleus, and liver, which are highly oxidative tissues, and our muscle data correlate tightly with values of resting blood flow (R2 = 0.99, P < 0.005) reported by Poole and associates (22). In this respect, it is notable that calcineurin, a mediator of muscle aerobic adaptation, which increases several hours after a bout of contractions (20, 21), activates NF-B in myocytes in vitro (2). Among skeletal muscles, basal NF-B activity also correlates with glutathione peroxidase activity (R2 = 0.92), as measured by Powers and coworkers (23, 24), which is consistent with the putative role of NF-B in regulating antioxidant defenses (29). Clearly, continued research is needed to determine the transcriptional targets and functional importance of constitutive NF-B signaling.
In conclusion, our present data demonstrate that fatiguing exercise inhibits NF-B activity in skeletal muscle. This finding may be important for conditions that promote muscle wasting, including cancer, spaceflight, human immunodeficiency virus or acquired immunodeficiency syndrome, and aging. The fact that exercise training reduces muscle wasting in these conditions (1, 6) emphasizes the importance of determining the underlying mechanism(s).
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GRANTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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ACKNOWLEDGMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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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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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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pathway in C2C12 skeletal muscle cells. J Biol Chem 277: 10100–10107, 2002.B-induced loss of MyoD messenger RNA: possible role in muscle decay and cachexia. Science 289: 2363–2366, 2000.B pathway in skeletal muscle during disuse atrophy. FASEB J 16: 529–538, 2002.B. Free Radic Biol Med 28: 1317–1327, 2000.[CrossRef][Web of Science][Medline]
B. FASEB J 15: 1169–1180, 2001./NF-B signaling in skeletal muscle myotubes. Antioxid Redox Signal 1: 97–104, 1999.[Medline]
increases ubiquitin conjugating activity in skeletal muscle by upregulating UbcH2/E220k. FASEB J 17: 1048–1057, 2003.B mediates the protein loss induced by TNF- in differentiated skeletal muscle myotubes. Am J Physiol Regul Integr Comp Physiol 279: R1165–R1170, 2000. regulates early differentiation of C2C12 myoblasts in an autocrine fashion. FASEB J 15: 1413–1415, 2001. mRNA expression is influenced by metabolic perturbation in exercising human skeletal muscle. J Appl Physiol 96: 189–194, 2004. suppresses adipocyte-specific genes and activates expression of preadipocyte genes in 3T3-L1 adipocytes: nuclear factor B activation by TNF- is obligatory. Diabetes 51: 1319–1336, 2002.B and AP-1 mediate transcriptional responses to oxidative stress in skeletal muscle cells. Free Radic Biol Med 31: 1405–1416, 2001.[CrossRef][Web of Science][Medline]This article has been cited by other articles:
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