Effect of cyclic stretch on beta1D-integrin expression and activation of FAK and RhoA.
Integrins play a pivotal role in proliferation, differentiation, and survival in skeletal and cardiac myocytes. The beta(1D)-isoform of the beta(1)-integrin is specifically expressed in striated skeletal muscle. However, little is known about the role and the mechanisms by which the splice variant beta(1D)-integrin regulates myogenesis and mechanotransduction. We observed that cyclic mechanical stretch increases beta(1D)-integrin protein levels and activates the downstream cytoskeletal signaling proteins focal adhesion kinase (FAK) and RhoA. Elimination of native beta(1D)-integrin expression by RNA interference in immature developing myoblasts abolished stretch-induced increases in FAK phosphorylation and further downregulated RhoA activity. Blocking of beta(1D)-integrin expression prevented myocellular fusion to form multinucleated mature myotubes. Restoration of human beta(1D)-integrin expression in beta(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 beta(1D)-integrin-deficient cells, suggesting signaling interactions between beta(1D)-integrin and neuronal NO synthase to mediate mechanotransduction and myogenesis in skeletal myocytes. These results suggest that, in addition to regulating differentiation, the beta(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.
Zhang, SJ; Truskey, GA; Kraus, WE
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