Mechanical strain has been demonstrated to be a potent stimulus of skeletal muscle hypertrophy. Furthermore others and we have also shown that mechanical stimuli can modulate muscle phenotype through specific changes in gene expression (1). The mechanisms by which alterations in mechanical environment are transduced into anabolic stimuli and specific changes in gene expression have still to be elucidated. We have recently produced evidence for the calcineurin/NFAT pathway and p38 playing a crucial role in stretch-induced alteration of phenotype in skeletal muscle cells (2,3). Studies have indicated, however, that the calcineurin pathway in not integral to muscle hypertrophy (4,5). In the present study we examined the role of other intracellular signalling pathways upon stretch induced anabolism. The inhibitor of mTor, Rapamycin (Rap) and the MEK/ERK inhibitor PD98059 (PD) both caused a marked reduction in stretch induced elevation of protein synthesis in C2C12 myotubes. We therefore examined the effects of static stretch upon components of both the Akt/mTor and ERK pathways that are known to regulate translation and protein synthesis. Passive stretch, suprisingly, had no effect upon the levels of activated Akt or mTor. In contrast the MAP Kinase ERK1/2 showed significant and rapid activation in response to stretch. We also observed that p70S6K a serine/threonine kinase involved in regulating translation was activated in response to stretch. Another key step in the translational control of protein synthesis occurs at the level of the eukaryotic initiation factor 4F (eIF4F) a major regulatory part of which eIF4E was shown to be activated by static stretch. eIF4E function is regulated in part by its association with the repressor protein 4E-BP1. We observed that this factor was activated in response to stretch, as was Mnk1 an activator of the eIF4F complex. We have also carried out studies on the effects of Rap and PD upon stretch-induced activation of the components of the stretch-induced pathway regulating protein synthesis. Interestingly Rap alone had no effect upon activated ERK levels but in combination with stretch produced a marked reduction. Surprisingly neither PD nor Rap had a significant effect upon 4E-BP1 levels with or without stretch. PD alone caused a fall in activated ERK levels but this was greatly exacerbated when combined with stretch. However PD in combination with stretch also produced a significant reduction in activated mTor. These data together suggest that the ERK pathway is the major regulator of protein synthesis in response to stretch but suggest that a more complex interaction with the mTor pathway may take place.