Mechanical stimuli and nutrients regulate rapamycin-sensitive signaling through distinct mechanisms in skeletal muscle.
The mammalian target of rapamycin (mTOR) has been identified as a growth factor and nutrient-sensitive molecule that controls the translational machinery and cell growth. Rapamycin-sensitive (RS) signaling events have also been shown to be necessary for mechanical load-induced growth of skeletal muscle, but the mechanisms involved in the mechanical activation of RS signaling are not known. The finding that mechanical stimuli induce nutrient uptake in skeletal muscle raises the possibility that mechanically induced RS signaling is mediated via a nutrient-dependent mechanism. To investigate this hypothesis, skeletal muscles (ex vivo) were stimulated with nutrients or intermittent mechanical stretch and the phosphorylation of p70S6k [P-p70(389)], PKB [P-PKB], mTOR [P-mTOR(2481)], and p38 [P-p38] was assessed. In comparison to vehicle-treated controls, both nutrient and mechanical stimuli induced P-p70(389), neither stimulus altered P-PKB or P-mTOR(2481), and only mechanical stimuli induced P-p38. The nutrient and mechanically induced increase in P-p70(389) was blocked by rapamycin, but only nutrient-induced signaling to P-p70(389) was blocked by wortmannin. Furthermore, the mechanically induced increase in P-p70(389) was not impaired by the removal of exogenous nutrients. Taken together, these results indicate that exogenous nutrients are not required for mechanically induced RS signaling and that nutrient and mechanical stimuli activate RS signaling through distinct upstream mechanisms.
Hornberger
Troy A
TA
Department of Bioengineering and Whitaker Institute of Biomedical Engineering, University of California, San Diego, 9500 Gilman Dr., La Jolla, California 92093-0412, USA.
Chien
Shu
S
D000596:Amino Acids / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D003470:Culture Media; D005947:Glucose / Q000378:metabolism; D006133:Growth Substances / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D010812:Physical Stimulation; D011494:Protein Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000378:metabolism / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases; D014325:Tromethamine / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000596:Amino Acids; D003470:Culture Media; D005947:Glucose; D006133:Growth Substances; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D014325:Tromethamine; D048051:p38 Mitogen-Activated Protein Kinases; C074097:Krebs-Henseleit solution; C546843:mTOR protein, mouse