Insulin Stimulation of Mitogen-activated Protein Kinase, p90rsk, and p70 S6 Kinase in Skeletal Muscle of Normal and Insulin-resistant Mice: IMPLICATIONS FOR THE REGULATION OF GLYCOGEN SYNTHASE

Pi-Yun Chang,Yannick Le Marchand-Brustel,Lynn A Cheatham,David E Moller

doi:10.1074/jbc.270.50.29928

Pi-Yun Chang, Yannick Le Marchand-Brustel + Show 2 more

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https://doi.org/10.1074/jbc.270.50.29928

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Abstract

Skeletal muscles from mice stimulated with insulin in vivo were used to evaluate relationships between the insulin receptor tyrosine kinase, mitogen-activated protein (MAP) kinase, p90rsk, p70 S6 kinase (p70S6k), and glycogen synthase. Two models of insulin resistance were also evaluated: (a) transgenic mice with a severe insulin receptor defect and (b) gold thioglucose (GTG) mice (obesity with minimal insulin receptor dysfunction). In normal mice, insulin stimulated MAP kinase (6-fold), p90rsk (RSK2, 5-fold), p70S6k (10-fold), and glycogen synthase (30-50% increase in fractional velocity). In transgenic mice, stimulation of MAP kinase and RSK2 were not detectable, whereas activation of p70S6k and glycogen synthase were preserved. In GTG mice, activation of MAP kinase, RSK2, p70S6k, and glycogen synthase were impaired. Since p70S6k and glycogen synthase were correlated, rapamycin was used to block p70S6k, and glycogen synthase activation was unaffected in normal mice; however, it was partially impaired in transgenic mice. (a) stimulation of p70S6k and glycogen synthase are selectively preserved in muscles with a severe insulin receptor kinase defect, indicating signal amplification in pathways leading to these effects; (b) MAP kinase-RSK2 and p70S6k activation are impaired in obese mice, suggesting multiple loci for postreceptor insulin resistance; (c) glycogen synthase was dissociated from MAP kinase and RSK2, indicating that they are not required for this effect of insulin; and (d) p70S6k is not essential for glycogen synthase activation, but it may participate in redundant signaling pathways leading to this effect of insulin.

Highlights

Skeletal muscles from mice stimulated with insulin in vivo were used to evaluate relationships between the insulin receptor tyrosine kinase, mitogen-activated protein (MAP) kinase, p90rsk, p70 S6 kinase (p70S6k), and glycogen synthase
Conclusions: (a) stimulation of p70S6k and glycogen synthase are selectively preserved in muscles with a severe insulin receptor kinase defect, indicating signal amplification in pathways leading to these effects; (b) MAP kinase-RSK2 and p70S6k activation are impaired in obese mice, suggesting multiple loci for postreceptor insulin resistance; (c) glycogen synthase was dissociated from MAP kinase and RSK2, indicating that they are not required for this effect of insulin; and (d) p70S6k is not essential for glycogen synthase activation, but it may participate in redundant signaling pathways leading to this effect of insulin
Impairment of the Insulin Receptor Tyrosine Kinase Proportionately Impairs Insulin-stimulated MAP Kinase—As we have previously observed [37], additional experiments showed that overexpression of mutant Thr1134 human insulin receptors in transgenic mice resulted in marked impairment of net muscle insulin receptor tyrosine kinase activity after in vivo administration of a maximally effective insulin dose (Fig. 1A)

Summary

Introduction

Skeletal muscles from mice stimulated with insulin in vivo were used to evaluate relationships between the insulin receptor tyrosine kinase, mitogen-activated protein (MAP) kinase, p90rsk, p70 S6 kinase (p70S6k), and glycogen synthase. Insulin stimulated MAP kinase (6-fold), p90rsk (RSK2, 5-fold), p70S6k (10-fold), and glycogen synthase (30 –50% increase in fractional velocity). Stimulation of MAP kinase and RSK2 were not detectable, whereas activation of p70S6k and glycogen synthase were preserved. In GTG mice, activation of MAP kinase, RSK2, p70S6k, and glycogen synthase were impaired. Important metabolic and mitogenic physiologic effects result from activation of the insulin receptor tyrosine kinase which leads to processes that are largely mediated by net increases or decreases in Ser/Thr phosphorylation of multiple proteins. Several lines of investigation suggest that p70S6k (via phosphorylation of ribosomal protein S6), MAP kinase (via phosphorylation of RSK, transcription factors, and proteins which modulate translation initiation), and RSK (via phosphorylation of transcription factors) have important roles in insulin-regulated cell proliferation and differentiation (16 –19)

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