Intracellular signaling specificity in response to uniaxial vs. multiaxial stretch: implications for mechanotransduction

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Abstract
Several lines of evidence suggest that muscle cells can distinguish between specific mechanical stimuli. To test this concept, we subjected C2C12myotubes to cyclic uniaxial or multiaxial stretch. Both types of stretch induced an increase in extracellular signal-regulated kinase (ERK) and protein kinase B (PKB/Akt) phosphorylation, but only multiaxial stretch induced ribosomal S6 kinase (p70S6k) phosphorylation. Further results demonstrated that the signaling events specific to multiaxial stretch (p70S6kphosphorylation) were elicited by forces delivered through the elastic culture membrane and were not due to greater surface area deformations or localized regions of large tensile strain. Experiments performed using medium that was conditioned by multiaxial stretched myotubes indicated that a release of paracrine factors was not sufficient for the induction of signaling to p70S6k. Furthermore, incubation with gadolinium(III) chloride (500 μM), genistein (250 μM), PD-98059 (250 μM), bisindolylmaleimide I (20 μM), or LY-294002 (100 μM ) did not block the multiaxial stretch-induced signaling to p70S6k. However, disrupting the actin cytoskeleton with cytochalasin D did block the multiaxial signaling to p70S6k, with no effect on signaling to PKB/Akt. These results demonstrate that specific types of mechanical stretch activate distinct signaling pathways, and we propose that this occurs through direct mechanosensory-mechanotransduction mechanisms and not through previously defined growth factor/receptor binding pathways.