Differential regulation of MAP kinase, p70(S6K), and Akt by contraction and insulin in rat skeletal muscle

To study the effects of contractile activity on mitogen-activated protein k inase (MAP kinase), p70 S6 kinase (p70(S6K)) and Akt kinase signaling in ra t skeletal muscle, hindlimb muscles were contracted by electrical stimulati on of the sciatic nerve for periods of 15 s to 60 min. Contraction resulted in a rapid and transient activation of Raf-l and MAP kinase kinase 1, a ra pid and more sustained activation of MAP kinase and the 90-kDa ribosomal S6 kinase 2, and a dramatic increase in c-fos mRNA expression. Contraction al so resulted in an apparent increase in the association of Raf-l with p21Ras , although stimulation of MAP kinase signaling occurred independent of Shc, IRS1, and IRS2 tyrosine phosphorylation or the formation of Shc/Grb2 or LR S1/Grb2 complexes. Insulin was considerably less effective than contraction in stimulating the MAP kinase pathway. However, insulin, but not contracti on, increased p70(S6K) and Akt activities in the muscle. These results demo nstrate that contraction-induced activation of the MAP kinase pathway is in dependent of proximal steps in insulin and/or growth factor-mediated signal ing, and that contraction and insulin have discordant effects with respect to the activation of the MAP kinase pathway vs, p70S6K and Akt. Of the nume rous stimulators of MAP kinase in skeletal muscle, contractile activity eme rges as a potent and physiologically relevant activator of MAP kinase signa ling, and thus activation of this pathway is likely to be an important mole cular mechanism by which skeletal muscle cells transduce mechanical and/or biochemical signals into downstream biological responses.