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

1 University of Illinois at Chicago, School of Kinesiology, Chicago, Illinois; and 2 Georgia Institute of Technology, School of Applied Physiology, Atlanta, Georgia Submitted 27 April 2004 ; accepted in final form 9 September 2004 Several lines of evidence suggest that muscle cells can distinguish between specific mechanical stimuli. To test this concept, we subjected C 2 C 12 myotubes 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 (p70 S6k ) phosphorylation. Further results demonstrated that the signaling events specific to multiaxial stretch (p70 S6k phosphorylation) 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 p70 S6k . 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 p70 S6k . However, disrupting the actin cytoskeleton with cytochalasin D did block the multiaxial signaling to p70 S6k , 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. growth; hypertrophy; muscle; strain; tension Address for reprint requests and other correspondence: K. Esser, Dept. of Physiology, Univ. of Kentucky, Albert B. Chandler Medical Center, 800 Rose St., Lexington, KY 40536-0298 (E-mail: karyn.esser{at}uky.edu )