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J. Biol. Chem. 277 (48): 46493-46503

© 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

Distinct Signaling Pathways Are Activated in Response to Mechanical Stress Applied Axially and Transversely to Skeletal Muscle Fibers*

Ashok Kumar, Imran Chaudhry, Michael B. Reid, and Aladin M. BoriekDagger

From the Department of Medicine, Baylor College of Medicine, Houston, Texas 77030

In the diaphragm muscle we tested the hypothesis that MAP kinase signaling pathways are activated by mechanical stress and such signaling pathways are dependent on the direction in which mechanical stress is applied. Although equal magnitudes of mechanical stress were applied axially and transversely a greater level of activation of ERK1/2, p38, Raf-1, p90 RSK, Elk-1, and the DNA binding activity of AP-1 transcription factor was produced when the muscle was stretched transversely than when stretched axially. A significant up-regulation in protein tyrosine phosphorylation was observed in axially or transversely loaded diaphragm muscles and the activation of ERK1/2 was completely inhibited by genistein (protein-tyrosine kinase inhibitor). Pretreatment of muscles with wortmannin (phosphoinositide 3-kinase inhibitor), TMB-8 (antagonist of intracellular calcium release), GF109203X (PKC inhibitor), or PD98059 (MEK1/2 inhibitor) blocked the activation of ERK1/2 kinases in response to axial but not to transverse loading. On the other hand, pretreatment of muscles with protein kinase A inhibitors H-7 and KT5720 completely suppressed the activation of ERK1/2 in response to transverse loading only. Taken together with the alterations of MAP kinases and the findings of elevations of downstream transcription targets, our data are consistent with two distinct MAP kinase signal transduction pathways in response to mechanical stress.

* This work was supported by National Institutes of Health Grants RO1-63134 and RO1-46230 (to A. B.) and HL45721 (to M. B. R.).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.

Dagger To whom correspondence should be addressed: Pulmonary and Critical Care, Suite 520B, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Fax: 713-798-3619; E-mail:

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

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