PHOSPHATIDYLINOSITOL 3-KINASE AND P70 S6 KINASE PARTICIPATE IN THE REGULATION OF PROTEIN-TURNOVER IN SKELETAL-MUSCLE BY INSULIN AND INSULIN-LIKE GROWTH-FACTOR-I

This study was designed to evaluate the role of phosphatidylinositol ( PI3) kinase, p70 S6 kinase (p70(S6R)), and mitogen-activated protein ( MAP) kinase in the regulation of muscle protein metabolism by insulin and insulin-like growth factor I (IGF-I). Wortmannin and LY294002 (inh ibitors of PI3 kinase) both abolished the stimulation of protein synth esis by insulin or IGF-I in epitrochlearis muscle incubated in vitro. LY294002 also totally reversed the antiproteolytic action of these hor mones. Although p70(S6K) activation by insulin and IGF-I may be mediat ed by PI3 kinase in epitrochlearis muscle, the specific inhibition of this kinase by rapamycin caused only partial (25%) inhibition of the s timulation of protein synthesis by these two hormones. Rapamycin had n o effect on proteolysis. Finally, insulin or IGF-I did not stimulate M AP kinase activity at any of the times tested (2-25 min), suggesting t hat this protein kinase was not directly involved in the regulation of muscle protein metabolism. These observations provide evidence that P I3 kinase and p70(S6K), but not MAP kinase, play a role in the regulat ion of muscle protein turnover by insulin or IGF-I.