Acute resistance exercise activates MAP kinase signaling in skeletal muscle of overweight women

Skeletal muscle atrophy results from disparate physiological conditions, including denervation, corticosteroid treatment, and aging. The purpose of this study was to describe and characterize the function of dual-specificity phosphatase 4 (Dusp4) in skeletal muscle after it was found to be induced in response to neurogenic atrophy. Quantitative PCR and Western blot analysis revealed that Dusp4 is expressed during myoblast proliferation but rapidly disappears as muscle cells differentiate. The Dusp4 regulatory region was cloned and found to contain a conserved E-box element that negatively regulates Dusp4 reporter gene activity in response to myogenic regulatory factor expression. In addition, the proximal 3′-untranslated region of Dusp4 acts in an inhibitory manner to repress reporter gene activity as muscle cells progress through the differentiation process. To determine potential function, Dusp4 was fused with green fluorescent protein, expressed in C2C12 cells, and found to localize to the nucleus of proliferating myoblasts. Furthermore, Dusp4 overexpression delayed C2C12 muscle cell differentiation and resulted in repression of a MAP kinase signaling pathway reporter gene. Ectopic expression of a Dusp4 dominant negative mutant blocked muscle cell differentiation and attenuated MAP kinase signaling by preferentially targeting the ERK1/2 branch, but not the p38 branch, of the MAP kinase signaling cascade in skeletal muscle cells. The findings presented in this study provide the first description of Dusp4 in skeletal muscle and suggest that Dusp4 may play an important role in the regulation of muscle cell differentiation by regulating MAP kinase signaling.

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Extracellular-regulated protein kinase cascades are activated in response to injury in human skeletal muscle

AJP Cell Physiology ◽

10.1152/ajpcell.1998.275.2.c555 ◽

1998 ◽

Vol 275 (2) ◽

pp. C555-C561 ◽

Cited By ~ 59

Author(s):

Doron Aronson ◽

Jørgen F. P. Wojtaszewski ◽

Anders Thorell ◽

Jonas Nygren ◽

David Zangen ◽

...

Keyword(s):

Skeletal Muscle ◽

Map Kinase ◽

Muscle Injury ◽

Human Skeletal Muscle ◽

Signaling Cascades ◽

Vastus Lateralis Muscle ◽

Kinase Signaling ◽

Transcriptional Responses ◽

Map Kinase Signaling ◽

Stimulation Of

The mitogen-activated protein (MAP) kinase signaling pathways are believed to act as critical signal transducers between stress stimuli and transcriptional responses in mammalian cells. However, it is not known whether these signaling cascades also participate in the response to injury in human tissues. To determine whether injury to the vastus lateralis muscle activates MAP kinase signaling in human subjects, two needle biopsies or open muscle biopsies were taken from the same incision site 30–60 min apart. The muscle biopsy procedures resulted in striking increases in dual phosphorylation of the extracellular-regulated kinases (ERK1 and ERK2) and in activity of the downstream substrate, the p90 ribosomal S6 kinase. Raf-1 kinase and MAP kinase kinase, upstream activators of ERK, were also markedly stimulated in all subjects. In addition, c-Jun NH2-terminal kinase and p38 kinase, components of two parallel MAP kinase pathways, were activated following muscle injury. The stimulation of the three MAP kinase cascades was present only in the immediate vicinity of the injury, a finding consistent with a local rather than systemic activation of these signaling cascades in response to injury. These data demonstrate that muscle injury induces the stimulation of the three MAP kinase cascades in human skeletal muscle, suggesting a physiological relevance of these protein kinases in the immediate response to tissue injury and possibly in the initiation of wound healing.

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IL-1β stimulates IL-6 production in cultured skeletal muscle cells through activation of MAP kinase signaling pathway and NF-κB

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00490.2002 ◽

2003 ◽

Vol 284 (5) ◽

pp. R1249-R1254 ◽

Cited By ~ 70

Author(s):

Guangjo Luo ◽

Dan D. Hershko ◽

Bruce W. Robb ◽

Curtis J. Wray ◽

Per-Olof Hasselgren

Keyword(s):

Skeletal Muscle ◽

Dna Binding ◽

Map Kinase ◽

Muscle Cells ◽

Binding Activity ◽

C2c12 Cells ◽

Luciferase Reporter ◽

Kinase Signaling ◽

Dna Binding Activity ◽

Map Kinase Signaling

Recent studies suggest that the skeletal muscle may be a significant site of IL-6 production in various conditions, including exercise, inflammation, hypoperfusion, denervation, and local muscle injury. The mediators and molecular mechanisms regulating muscle IL-6 production are poorly understood. We tested the hypothesis that IL-6 production in muscle cells is regulated by IL-1β and that mitogen-activated protein (MAP) kinase signaling and NF-κB activation are involved in IL-1β-induced IL-6 production. Cultured C2C12 cells, a mouse skeletal muscle cell line, were treated with different concentrations (0.1–2 ng/ml) of IL-1β in the absence or presence of the p38 MAP kinase inhibitor SB-208350 or the p42/44 inhibitor PD-98059. Protein and gene expression of IL-6 were determined by ELISA and real-time PCR, respectively. NF-κB DNA binding activity was determined by electrophoretic mobility shift assay and by transfecting myocytes with a luciferase reporter plasmid containing a promoter construct with multiple repeats of NF-κB binding site. Treatment of myotubes with IL-1β resulted in a dose- and time-dependent increase of IL-6 production accompanied by an ∼25-fold increase in IL-6 mRNA levels. IL-1β stimulated NF-κB DNA binding activity and gene activation. SB-208350 and PD-98059 inhibited the increase in IL-6 production induced by IL-1β. The present results support the concept that skeletal muscle is an important site of IL-6 production. In addition, the results suggest the IL-1β regulates muscle IL-6 production at least in part by activating the MAP kinase pathway and NF-κB.

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Differential regulation of MAP kinase, p70S6K, and Akt by contraction and insulin in rat skeletal muscle

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1999.276.5.e870 ◽

1999 ◽

Vol 276 (5) ◽

pp. E870-E878 ◽

Cited By ~ 40

Author(s):

Daniel J. Sherwood ◽

Scott D. Dufresne ◽

Jeffrey F. Markuns ◽

Bentley Cheatham ◽

David E. Moller ◽

...

Keyword(s):

Skeletal Muscle ◽

Map Kinase ◽

Contractile Activity ◽

Kinase Signaling ◽

Rat Skeletal Muscle ◽

S6 Kinase ◽

Map Kinase Signaling ◽

Map Kinase Pathway ◽

Kinase Pathway ◽

Stimulation Of

To study the effects of contractile activity on mitogen-activated protein kinase (MAP kinase), p70 S6 kinase (p70S6K), and Akt kinase signaling in rat skeletal muscle, hindlimb muscles were contracted by electrical stimulation of the sciatic nerve for periods of 15 s to 60 min. Contraction resulted in a rapid and transient activation of Raf-1 and MAP kinase kinase 1, a rapid and more sustained activation of MAP kinase and the 90-kDa ribosomal S6 kinase 2, and a dramatic increase in c- fos mRNA expression. Contraction also resulted in an apparent increase in the association of Raf-1 with p21Ras, although stimulation of MAP kinase signaling occurred independent of Shc, IRS1, and IRS2 tyrosine phosphorylation or the formation of Shc/Grb2 or IRS1/Grb2 complexes. Insulin was considerably less effective than contraction in stimulating the MAP kinase pathway. However, insulin, but not contraction, increased p70S6K and Akt activities in the muscle. These results demonstrate that contraction-induced activation of the MAP kinase pathway is independent of proximal steps in insulin and/or growth factor-mediated signaling, and that contraction and insulin have discordant effects with respect to the activation of the MAP kinase pathway vs. p70S6K and Akt. Of the numerous stimulators of MAP kinase in skeletal muscle, contractile activity emerges as a potent and physiologically relevant activator of MAP kinase signaling, and thus activation of this pathway is likely to be an important molecular mechanism by which skeletal muscle cells transduce mechanical and/or biochemical signals into downstream biological responses.

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Effects of exercise and insulin on mitogen-activated protein kinase signaling pathways in rat skeletal muscle

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1996.271.2.e403 ◽

1996 ◽

Vol 271 (2) ◽

pp. E403-E408 ◽

Cited By ~ 60

Author(s):

L. J. Goodyear ◽

P. Y. Chang ◽

D. J. Sherwood ◽

S. D. Dufresne ◽

D. E. Moller

Keyword(s):

Skeletal Muscle ◽

Protein Kinase ◽

Map Kinase ◽

Signaling Pathways ◽

Mammalian Cells ◽

Mitogen Activated Protein Kinase ◽

Kinase Signaling ◽

Rat Skeletal Muscle ◽

Map Kinase Signaling ◽

Mitogen Activated Protein

Studies in mammalian cells have established the existence of at least three distinct mitogen-activated protein kinase (MAP kinase) signaling pathways that are activated by a variety of growth factors and/or environmental stressors. We determined whether physical exercise, a physiological stressor, and insulin, a metabolic stimulator and growth factor, activate the c-jun NH2-terminus kinase (JNK), the p38 kinase, and/or the extracellular regulatory kinases (ERK; p42MAPK and p44MAPK) signaling pathways in rat skeletal muscle. Animals were studied immediately after running on a motorized treadmill for 10-60 min (20 m/min, 10% grade) or 5-30 min after an intraperitoneal injection of insulin (20 U/rat). Exercise increased skeletal muscle JNK activity by two- to threefold throughout the time course studied, whereas insulin did not significantly increase JNK activity. The p38 activity was slightly stimulated by exercise and not by insulin. The ERK kinase pathway, as assessed by ribosomal S6 kinase-2 activity assays and phosphospecific p42MAPK/p4NAPK immunoblotting, was stimulated by both exercise and insulin. These data are the first demonstration of exercise stimulating multiple intracellular signaling pathways in skeletal muscle. Activation of these MAP kinase signaling pathways may mediate changes in skeletal muscle growth and metabolism that occur in response to exercise.

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Skeletal muscle contractile activity in vitro stimulates mitogen-activated protein kinase signaling

AJP Cell Physiology ◽

10.1152/ajpcell.1999.277.4.c701 ◽

1999 ◽

Vol 277 (4) ◽

pp. C701-C707 ◽

Cited By ~ 63

Author(s):

Tatsuya Hayashi ◽

Michael F. Hirshman ◽

Scott D. Dufresne ◽

Laurie J. Goodyear

Keyword(s):

Skeletal Muscle ◽

Map Kinase ◽

Neurotransmitter Release ◽

Contractile Activity ◽

Kinase Signaling ◽

Map Kinase Signaling ◽

Mitogen Activated Protein ◽

Kinase Phosphorylation ◽

Muscle Contractile

Physical exercise is a potent stimulator of mitogen-activated protein (MAP) kinase signaling. To determine if this activation is secondary to systemic responses to exercise or due to muscle contractile activity per se, an isolated muscle preparation was developed. Contractile activity in vitro significantly increased p44MAPK and p42MAPK phosphorylation by 2.9- and 2.4-fold, respectively. Contraction-stimulated MAP kinase phosphorylation was not decreased in the presence ofd-tubocurarine or calphostin C, suggesting that neither neurotransmitter release nor diacylglycerol-sensitive protein kinase C mediates the contraction-induced activation of this signaling cascade. However, PD-98059, an inhibitor of MAP kinase kinase (MEK), inhibited the contraction-induced increases in MAP kinase phosphorylation. PD-98059 did not alter contraction-induced increases in glucose uptake or glycogen synthase activity, demonstrating that MAP kinase signaling is not necessary for these important metabolic effects of contractile activity in skeletal muscle. These data suggest that contractile activity of the skeletal muscle fibers per se, and not responses to neurotransmitter release, hormones, or other systemic factors, is responsible for the stimulation of MAP kinase signaling with physical exercise.

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