Cyclic mechanical strain inhibits skeletal myogenesis through activation of focal adhesion kinase, Rac-1 GTPase, and NF-κB transcription factor

Ashok Kumar, Ryan Murphy, Prema Robinson, Lei Wei, Aladin M. Boriek

Research output: Contribution to journalArticle

86 Citations (Scopus)

Abstract

Myogenesis is a multistep developmental program that generates and regenerates skeletal muscles. Several extracellular factors have been identified that participate in the regulation of myogenesis. Although skeletal muscles are always subjected to mechanical stress in vivo, the role of mechanical forces in the regulation of myogenesis remains unknown. We have investigated the molecular mechanisms by which cyclic mechanical strain modulates myogenesis. Application of cyclic mechanical strain using the computer-controlled Flexcell Strain Unit increased the proliferation of C2C12 cells and inhibited their differentiation into myotubes. Cyclic strain increased the activity of cyclin-dependent kinase 2 (cdk2) and the cellular level of cyclin A, and inhibited the expression of myosin heavy chain and formation of myotubes in C2C12 cultures. The activity of nuclear factor-kappa B (NF-κB) transcription factor and the expression of NF-κB-regulated genes, cyclin D1 and IL-6, were augmented in response to mechanical strain. Cyclic strain also increased the activity of Rho GTPases, especially Rac-1. The inhibition of Rho GTPases activity, by overexpression of Rho GDP dissociation inhibitor (Rho-GDI), inhibited the strain-induced activation of NF-κB in C2C12 cells. Overexpression of either NF-κB inhibitory protein IκBαΔN (a degradation resistant mutant IκBα) or Rho-GDI blocked the strain-induced proliferation of C2C12 cells. Furthermore, overexpression of FRNK, a dominant negative mutant of focal adhesion kinase (FAK), inhibited the strain-induced proliferation of C2C12 cells. Our study demonstrates that cyclic mechanical strain inhibits myogenesis through the activation of FAK, Rac-1, and NF-κB.

Original languageEnglish (US)
Pages (from-to)1524-1535
Number of pages12
JournalFASEB Journal
Volume18
Issue number13
DOIs
StatePublished - Oct 2004
Externally publishedYes

Fingerprint

Focal Adhesion Kinase 1
non-specific protein-tyrosine kinase
Focal Adhesion Protein-Tyrosine Kinases
Muscle Development
NF-kappa B
muscle development
GTP Phosphohydrolases
guanosinetriphosphatase
Transcription Factors
transcription factors
Chemical activation
Guanine Nucleotide Dissociation Inhibitors
rho GTP-Binding Proteins
Skeletal Muscle Fibers
Cell Proliferation
Skeletal Muscle
bcl-1 Genes
Cyclin-Dependent Kinase 2
Cyclin A
cell proliferation

Keywords

  • C2C12 cells
  • Cyclic stretch
  • FAK
  • NF-kappa B
  • Rac-1
  • Skeletal myogenesis

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology

Cite this

Cyclic mechanical strain inhibits skeletal myogenesis through activation of focal adhesion kinase, Rac-1 GTPase, and NF-κB transcription factor. / Kumar, Ashok; Murphy, Ryan; Robinson, Prema; Wei, Lei; Boriek, Aladin M.

In: FASEB Journal, Vol. 18, No. 13, 10.2004, p. 1524-1535.

Research output: Contribution to journalArticle

Kumar, Ashok ; Murphy, Ryan ; Robinson, Prema ; Wei, Lei ; Boriek, Aladin M. / Cyclic mechanical strain inhibits skeletal myogenesis through activation of focal adhesion kinase, Rac-1 GTPase, and NF-κB transcription factor. In: FASEB Journal. 2004 ; Vol. 18, No. 13. pp. 1524-1535.
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