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GROWTH, DIFFERENTIATION, AND APOPTOSIS

Effect of cyclic stretch on _1D-integrin expression and activation of FAK and RhoA

¹Department of Biomedical Engineering, Duke University, and ²Division of Cardiology, Department of Medicine and ³Department of Cell Biology, Duke University Medical Center, Durham, North Carolina

Submitted 18 September 2006 ; accepted in final form 10 January 2007

Integrins play a pivotal role in proliferation, differentiation, and survival in skeletal and cardiac myocytes. The _1D-isoform of the ₁-integrin is specifically expressed in striated skeletal muscle. However, little is known about the role and the mechanisms by which the splice variant _1D-integrin regulates myogenesis and mechanotransduction. We observed that cyclic mechanical stretch increases _1D-integrin protein levels and activates the downstream cytoskeletal signaling proteins focal adhesion kinase (FAK) and RhoA. Elimination of native _1D-integrin expression by RNA interference in immature developing myoblasts abolished stretch-induced increases in FAK phosphorylation and further downregulated RhoA activity. Blocking of _1D-integrin expression prevented myocellular fusion to form multinucleated mature myotubes. Restoration of human _1D-integrin expression in _1D-integrin-deficient cells partially restored myotube formation. The onset of myofusion also requires the generation of nitric oxide (NO). The release of NO affects cytoskeletal proteins by mediating RhoA activity and protein degradation. Our previous study demonstrated that stretch-induced NO positively modulates mechanical properties of differentiating skeletal myocytes. We found a significant decrease in NO production and apparent elastic modulus in _1D-integrin-deficient cells, suggesting signaling interactions between _1D-integrin and neuronal NO synthase to mediate mechanotransduction and myogenesis in skeletal myocytes. These results suggest that, in addition to regulating differentiation, the _1D-integrin isoform plays a critical role in the response of skeletal myoblasts to cyclic stretch by activating the downstream components of FAK and RhoA activity and affecting NO release.

focal adhesion kinase; RhoA activity; mechanotransduction; skeletal myocytes

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