1 Research Division, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston; and 2 Department of Health Sciences, Sargent College of Health and Rehabilitation Sciences, Boston University, Boston, Massachusetts 02215
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ABSTRACT |
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Physical exercise and contraction increase c-Jun NH2-terminal kinase (JNK) activity in rat and human skeletal muscle, and eccentric contractions activate JNK to a greater extent than concentric contractions in human skeletal muscle. Because eccentric contractions include a lengthening or stretch component, we compared the effects of isometric contraction and static stretch on JNK and p38, the stress-activated protein kinases. Soleus and extensor digitorum longus (EDL) muscles dissected from 50- to 90-g male Sprague-Dawley rats were subjected to 10 min of electrical stimulation that produced contractions and/or to 10 min of stretch (0.24 N tension, 20-25% increase in length) in vitro. In the soleus muscle, contraction resulted in a small, but significant, increase in JNK activity (1.8-fold above basal) and p38 phosphorylation (4-fold). Static stretch had a much more profound effect on the stress-activated protein kinases, increasing JNK activity 19-fold and p38 phosphorylation 21-fold. Increases in JNK activation and p38 phosphorylation in response to static stretch were fiber-type dependent, with greater increases occurring in the soleus than in the EDL. Immunohistochemistry performed with a phosphospecific antibody revealed that activation of JNK occurred within the muscle fibers. These studies suggest that the stretch component of a muscle contraction may be a major contributor to the increases in JNK activity and p38 phosphorylation observed after exercise in vivo.
contraction; extracellular signal-regulated kinase; soleus; extensor digitorum longus
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INTRODUCTION |
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STATIC STRETCH of smooth, cardiac, and skeletal muscle cells in vitro or in vivo results in well-defined changes in cellular growth, morphology, and metabolism (30). Vandenburgh and Kaufman (32) demonstrated that static stretch induces a hypertrophic response in cultured chick skeletal muscle cells, providing the first evidence that skeletal muscle cells are able to respond to external mechanical tension in the complete absence of neuronal or hormonal factors. Many studies also have shown that the mRNA levels of several genes, including insulin-like growth factor I (IGF-I) (9, 22), fibroblast growth factor (23), myogenic regulatory factor (20), and c-jun (9), are increased by stretch in skeletal muscle. In addition, muscle IGF-I (9, 25), prostaglandins (31), and p125FAK (7) protein abundance increases in response to stretch. The mechanosensory mechanisms that are responsible for changes in gene transcription and expression in skeletal muscle are unknown, but it has been hypothesized that externally applied forces influence nuclear events either directly or indirectly via the stimulation of signaling molecules (30).
An acute bout of physical exercise and contraction of rat hindlimb muscles produced by electrical stimulation of the sciatic nerve in situ can activate intracellular signaling pathways and gene transcription in skeletal muscle (1, 2, 11, 33). The mitogen-activated protein kinase (MAPK) family of intracellular signaling proteins, including the c-Jun NH2-terminal kinases (JNKs) (1, 2, 11), p38 kinases (11, 33), and extracellular signal-regulated protein kinases (ERKs) (2, 15, 33), is consistently activated in response to contraction or exercise in rat (2, 11, 15) and human (1, 33) skeletal muscle. We also have shown that an acute bout of moderate intensity cycling exercise can increase c-jun mRNA in human skeletal muscle (1) and that in situ contractions can increase c-jun (2) and c-fos mRNA (29) in rat skeletal muscle. Therefore, similar to stretch, several transcriptional factors are upregulated with contraction, and it is possible that intracellular signaling through the MAPK proteins facilitates this action.
Skeletal muscle will shorten, remain isometric, or lengthen in accordance with the external load and the force developed by the muscle (6). Physical exercise that stretches the muscle or consists of eccentric (lengthening) contractions provides a significant source of mechanical stress and can result in more profound changes in muscle morphology compared with concentric (shortening) contractions, including greater skeletal muscle injury, remodeling, and hypertrophy (8, 10). Because eccentric contractions increase JNK activity in human skeletal muscle to a greater extent (15-fold) than concentric contractions (3.5-fold) (3), we hypothesized that the stretch or lengthening component of contraction is a stimulus for JNK activation.
In this study, we utilized an isolated skeletal muscle preparation to investigate the effects of contraction and static stretch on the MAPK family of signaling proteins, including JNK, p38, and ERK. The in vitro incubation system allowed us to characterize the effects of contraction and stretch on MAPK signaling in the absence of hormonal or neuronal factors. Our results demonstrate that static stretch results in a much more dramatic activation of JNK activity and p38 phosphorylation than isometric contractions in rat skeletal muscle.
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METHODS |
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Materials.
Anti-JNK1 and p38 antibodies were purchased from Santa Cruz
Biotechnology (Santa Cruz, CA), phosphospecific JNK antibody was from
Promega (Madison, WI), phosphospecific p38 antibody was from New
England Biolabs (Beverly, MA), phosphospecific ERK antibody was from
Quality Controlled Biochemicals (Hopkinton, MA), and FITC-conjugated
anti-rabbit IgG was from Jackson Laboratories (West Grove, PA). Protein
A-agarose was purchased from Pierce Chemical (Rockford, IL), and
[-32P]ATP was from DuPont NEN (Boston, MA).
Horseradish peroxidase-conjugated anti-rabbit IgG whole antibody and
enhanced chemiluminescence kit were purchased from Amersham Life
Sciences (Arlington Heights, IL), dye reagent for determination of
protein concentrations was from Bio-Rad (Hercules, CA), and all other
chemicals were purchased from Sigma Chemical (St. Louis, MO).
Muscle incubation. Male Sprague-Dawley rats (Taconic Laboratories, Germantown, NY) weighing 50-90 g were fasted overnight before the study. Rats were killed by cervical dislocation, the legs were removed, and soleus and/or extensor digitorum longus (EDL) muscles were dissected. Tendons from both ends of the muscle were tied with suture (silk 4-0) and mounted at resting tension before preincubation. The dissection and mounting procedures were performed rapidly and with care to prevent stretching or tearing of the muscle. The muscle was maintained at resting length throughout the experimental procedure from the time of dissection to the final incubation.
For basal, contraction, and stretch treatments, muscles were preincubated for 40 min in Krebs-Ringer bicarbonate (KRB) 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 at 37°C) containing 2 mM pyruvate. Muscles were first preincubated in 10 ml of KRB buffer for 10 min and then preincubated in 6 ml of KRB buffer for 30 min. After preincubation, all muscles were placed between two electrodes on a force transducer and incubated in 4 ml of KRB buffer. Resting tension of 0.5 g (optimal length Lo) was applied to each muscle for 10 min before initiation of contraction or stretch. Contractions were produced by stimulating the muscle with a Grass S88 pulse generator (Grass Instruments, Quincy, MA). The following protocol was used to induce isometric contractions: train rate = 0.033 sMuscle processing.
Soleus and EDL muscles were homogenized (Polytron; Brinkmann
Instruments, Westbury, NY) in ice-cold lysis buffer containing 20 mM
HEPES, pH 7.4, 2 mM EGTA, 50 mM -glycerophosphate, 1 mM dithiothreitol, 1 mM Na3VO4, 1% Triton X-100,
10% glycerol, 10 mM leupeptin, 3 mM benzamidine, 5 mM pepstatin A, 10 mg/ml aprotinin, and 1 mM phenylmethylsulfonyl fluoride. Homogenates
were rotated for 1 h at 4°C and then centrifuged at 13,000 g for 68 min at 4°C. Supernatants were frozen in liquid
nitrogen and stored at
80°C. Protein concentrations of the muscle
extracts were measured with the Bradford method (4) using
a kit purchased from Bio-Rad (Hercules, CA) and bovine serum albumin
(BSA) as a standard.
JNK activity assay.
JNK activity was assessed with the use of an in vitro immune complex
assay as previously described in detail (2, 3). Briefly,
muscle lysates (250 µg protein) were immunoprecipitated with 1.0 µg
of anti-JNK1 and 50 µl of prewashed protein A beads. After
immunoprecipitation, the JNK immune complexes were washed and then
resuspended in 30 µl of kinase assay buffer, and kinase reactions
were carried out in a reaction mixture containing 3 µg of inactive
glutathione S-transferase-c-Jun as substrate, 3.75 mM
MgCl2, 50 µM ATP, and 10 µCi [-32P]ATP
for 30 min at 30°C.
Immunoblotting.
To determine p38 and ERK phosphorylation, equal amounts of muscle
lysate total protein were resolved in 10% SDS-polyacrylamide gels,
transferred to nitrocellulose membranes, and blocked in Tris-buffered
saline (pH 7.8) plus NaN3 containing 2.5-5% BSA for
2 h at room temperature. The membranes then were incubated overnight at 4°C with either a phosphospecific p38 antibody
(1:1,000), which recognizes p38 phosphorylated at Tyr-182, or a
phosphospecific ERK antibody (1:1,000), which recognizes ERK1 (p44
MAPK) and ERK2 (p42 MAPK) when they are dually phosphorylated at
Thr-202 and Tyr-204. The phosphospecific p38 antibody does not
distinguish between the different isoforms of p38 in rat skeletal
muscle when direct Western blotting methods are used. Membranes were
probed with horseradish peroxidase-conjugated anti-rabbit IgG (1:2,000) for 1 h at room temperature, and immunoreactive proteins were detected using enhanced chemiluminescence. After determination of p38
phosphorylation, membranes were incubated in stripping buffer (1 M
Tris, pH 6.7, 10% SDS, and -mercaptoethanol) for 30 min at 50°C,
washed extensively, and used to determine either p38 protein expression
with a p38 antibody (1:2,000) or JNK protein expression with a JNK1
(1:2,000) antibody.
Immunohistochemistry.
Immediately after basal incubation or stretch (0.24 N tension) in
vitro, soleus muscles were frozen in isopentane precooled by liquid
nitrogen. Frozen sections (8 µm) were obtained, fixed in cold acetone
(20°C) for 10 min, and blocked with phosphate-buffered saline (PBS,
pH 7.4) containing 0.5% BSA and 0.5% Triton-X for 20 min. The
sections were then incubated with phosphospecific JNK antibody (1:100)
for 1 h at room temperature, rinsed in PBS, and incubated with
FITC-conjugated anti-rabbit IgG (1:100) for 1 h at room
temperature. Muscle fiber nuclei also were stained with propidium
iodide (10 µg/ml). After a final wash in PBS, sections were mounted
with Vectashield mounting medium (Vector Laboratories, Burlingame, CA)
and then visualized with the use of a confocal microscope (Carl Zeiss,
Thornwood, NY) at ×250 magnification.
Statistical analysis. All data are expressed as means ± SE. Data were compared by using either one-way ANOVA or Kruskal-Wallis one-way ANOVA on ranks. Tukey's post hoc test or Dunn's method was used to detect whether differences existed. The differences between groups were accepted to be significant at P < 0.05.
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RESULTS |
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Time course of contraction-induced MAPK activation
in vitro.
To determine the optimal time course for MAPK activation in vitro,
soleus muscles were contracted in vitro for 0, 0.5, 1.5, 5, and 10 min.
Longer time points were not assessed because of the inability of
muscles to adequately contract due to fatigue. Figure
1 shows representative reaction products
from the JNK activity assay and representative immunoblots for p38 and
ERK phosphorylation. JNK activity was maximal after 10 min of
contraction, whereas p38 and ERK phosphorylation were maximal after 5 min of contraction (Fig. 1).
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Comparison of contraction and static stretch on MAPK
activities.
While 10 min of contraction caused a modest increase in JNK activity
(1.8-fold above basal), static stretch for a comparable 10-min time
period greatly increased JNK activity to 19-fold above basal in soleus
muscle (Fig. 2A). The effects
of contraction or stretch on p38 and ERK phosphorylation also were
examined in soleus muscle. p38 phosphorylation was increased 4- and
21-fold in response to contraction and stretch, respectively (Fig.
2B). ERK1 and ERK2 phosphorylation were increased 1.7- and
1.5-fold above basal, respectively, after contraction (Fig.
2C). However, in contrast to the dramatic increases in JNK
activity and p38 phosphorylation observed with stretch, ERK1/2
phosphorylation was only increased ~2-fold. These results demonstrate
that static stretch in vitro has differential effects on the activation
of the MAPK proteins.
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Increasing tension by static stretch.
To determine whether there is a dose-response relationship between the
extent of static stretch and JNK activity and/or p38 phosphorylation,
we examined the effect of incremental increases in stretch on the
stress-activated protein kinases in soleus muscle. Because soleus
muscle is predominantly a type I (slow twitch) muscle, activation and
phosphorylation also were measured in the EDL, a predominantly type II
(fast twitch) muscle with distinct metabolic properties. Tension of
0.06 N did not significantly increase JNK activity in the soleus or
EDL, whereas tension of 0.12 or 0.24 N increased JNK activity in both
muscles (Fig. 3). There was a different
response to 0.24 N of stretch in the EDL muscle compared with that in
the soleus muscle. A dramatic increase in JNK activity was observed
between 0.12 and 0.24 N of stretch in the soleus, whereas no additional
increase was observed between 0.12 and 0.24 N in the EDL. JNK protein
expression was not acutely altered after stretch in either muscle type
(Fig. 3, A and B). However, these immunoblotting
studies do suggest that JNK expression is greater in the soleus than in
the EDL muscle.
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Immunohistochemistry of JNK following stretch.
To determine whether skeletal muscle was the specific cellular site for
JNK activation, we visualized JNK in soleus muscle cross sections using
a phosphospecific JNK antibody. Only minimal JNK phosphorylation was
detected in the basal state, whereas 10 min of stretch (0.24 N) clearly
increased phosphorylation of JNK within the muscle fibers (Fig.
6). JNK phosphorylation was not detected
in negative control sections incubated in the absence of primary
antibody (data not shown).
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DISCUSSION |
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This study demonstrates that static stretch markedly increases the activation of the stress-activated protein kinases JNK and p38 in rat skeletal muscle. The degree of JNK activation and p38 phosphorylation following stretch is remarkably higher than the increases that are observed in response to contraction in vitro. JNK activity and p38 phosphorylation are also higher after stretch than after treadmill running exercise in rat skeletal muscle (11) or cycling exercise in human skeletal muscle (1, 33). However, the extent of JNK activation following stretch is strikingly similar to the increase observed with eccentric exercise (3). These studies support a model whereby both stretch and eccentric contractions stimulate JNK activity via the same mechanism and suggest that the stretch component of a muscle contraction is an important activator of JNK during exercise. The effect of stretch on the stress-activated protein kinases appears to be specific for these molecules because the ERKs were found to be minimally phosphorylated in response to stretch.
The degree of stretch induced by 0.24 N of tension resulted in a robust increase in p38 phosphorylation in soleus muscle (21-fold increase above basal). This magnitude of phosphorylation was unexpected because previous studies conducted in vitro have reported less dramatic increases in phosphorylation with stretch. For example, stretching cells in culture results in no change in p38 phosphorylation in cardiac fibroblasts in culture (21), a modest 2- to 3-fold increase in cardiomyocytes (19, 28), and a 12-fold increase in mesangial cells (16). The variable responses to stretch may be due to complex regulation of p38, whereby phosphorylation and activation are dependent on the cell type examined, the isoform of p38 activated, or the intensity of the stretch applied.
Despite similar tension (0.24 N) and lengthening (4 mm) of soleus and EDL muscles, JNK activity and p38 phosphorylation were much higher in the soleus, a predominantly slow-twitch muscle, than in the EDL, a predominantly fast-twitch muscle. Numerous cellular, structural, and metabolic factors could account for the differences in activation between the soleus and EDL with stretch, including greater relative tension within individual muscle fibers as a result of structural differences, extent of myofibrillar damage as a consequence of differences in tension, the degree of JNK and p38 protein expression, or the oxidative state of the muscles. Because fiber length of the EDL (10 mm) is similar to that of the soleus (12 mm) and the pennation angle in the soleus muscle (5°) is almost identical to that in the EDL muscle (3.5°) (5), it is unlikely that muscle architecture is responsible for the differences observed. Another possible mechanism for the differences is the higher level of protein expression in the soleus vs. the EDL muscle. Consistent with this observation, our preliminary studies have also demonstrated that, under basal conditions, JNK expression and activity are ~50% higher in red compared with white gastrocnemius rat muscle (Boppart MD, Fielding RA, and Goodyear LJ, unpublished data). Although the higher expression of JNK may account for the greater activation of JNK in the soleus muscle, protein abundance cannot explain the greater increase in p38 phosphorylation in soleus because there were actually lower levels of p38 in soleus muscles than in EDL. Therefore, factors other than protein expression or muscle structure may account for the marked increases in JNK activity and p38 phosphorylation observed in the soleus compared with the EDL with 0.24 N of tension.
Previous studies have suggested that mechanical tension alone can regulate cell growth and metabolism and that intracellular signaling proteins may link changes in tension to these cellular adaptations (32). In the current study, both JNK activity and p38 phosphorylation were increased after stretch in the absence of systemic factors, suggesting that mechanical force alone is a primary stimulus for activation. However, because autocrine and/or paracrine factors are known to be released from muscle after contraction and stretch, it cannot be stated conclusively that such factors are not involved in the stretch-mediated increases in the stress-activated protein kinases (27, 14). We conducted preliminary studies in which freshly isolated, unstretched soleus muscles were incubated in buffers that previously had been used for either contraction or stretch. Interestingly, there was a trend toward a 2- to 3-fold increase in JNK activity in contraction- and stretch-conditioned buffers (Boppart MD, Fielding RA, and Goodyear LJ, unpublished data). Studies are ongoing to more precisely define the potential role and importance of paracrine and autocrine factors in the activation of JNK and p38 with contraction and/or stretch.
Stretch has been shown to increase JNK activity in a variety of cell lines, including cardiomyocytes (27, 21), mesangial cells (17), and vascular smooth muscle cells (14). Phosphorylation of JNK on specific threonine and tyrosine residues leads to increased kinase activity in the cytosol and translocation to the nucleus. The activated JNK molecule can then phosphorylate transcription factors, such as c-Jun (26) and ATF-2 (13), and these transcription factors initiate transcription of genes such as cyclooxygenase-2 (COX-2) (12) and collagenase (18). Because stretch can activate JNK and cause the induction of genes such as COX-2 in smooth muscle (24), it is likely that JNK is a mechanosensory signaling molecule that can respond to mechanical stress and subsequently regulate gene transcription in skeletal muscle.
In summary, this study provides the first evidence for the activation of the stress-activated protein kinases in rat soleus muscle in vitro after both contraction and static stretch. Visualization of JNK activation within the skeletal muscle fibers with the use of immunohistochemistry also is demonstrated for the first time. These data, together with results from our previous study showing that eccentric contractions markedly activate JNK in human skeletal muscle, suggest that the stretch component of a muscle contraction may be an important mediator for the increases in JNK and p38 activation observed in vivo.
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ACKNOWLEDGEMENTS |
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This work was supported by National Institute of Arthritis and Musculoskeletal and Skin Diseases Grant AR-42238 (to L. J. Goodyear), an American College of Sports Medicine Foundation Grant (to M. D. Boppart), and a National Research Training Center Grant from National Institute of Diabetes and Digestive and Kidney Diseases (Joslin Diabetes Center, Grant T32 DK-07260-22, to M. D. Boppart). R. A. Fielding is a Brookdale National Fellow at Boston University.
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FOOTNOTES |
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Address for reprint requests and other correspondence: L. J. Goodyear, Research Division, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215 (E-mail: laurie.goodyear{at}joslin.harvard.edu).
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.
Received 10 January 2000; accepted in final form 8 September 2000.
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