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. 2007 Aug 1;582(Pt 3):1289-301.
doi: 10.1113/jphysiol.2007.136614. Epub 2007 May 31.

Exercise improves phosphatidylinositol-3,4,5-trisphosphate responsiveness of atypical protein kinase C and interacts with insulin signalling to peptide elongation in human skeletal muscle

Christian Frøsig  1 , Mini P Sajan, Stine J Maarbjerg, Nina Brandt, Carsten Roepstorff, Jørgen F P Wojtaszewski, Bente Kiens, Robert V Farese, Erik A Richter
Affiliations

Exercise improves phosphatidylinositol-3,4,5-trisphosphate responsiveness of atypical protein kinase C and interacts with insulin signalling to peptide elongation in human skeletal muscle

Christian Frøsig et al. J Physiol. .

Abstract

We investigated if acute endurance-type exercise interacts with insulin-stimulated activation of atypical protein kinase C (aPKC) and insulin signalling to peptide chain elongation in human skeletal muscle. Four hours after acute one-legged exercise, insulin-induced glucose uptake was approximately 80% higher (N = 12, P < 0.05) in previously exercised muscle, measured during a euglycaemic-hyperinsulinaemic clamp (100 microU ml(-1)). Insulin increased (P < 0.05) both insulin receptor substrate (IRS)-1 and IRS-2 associated phosphatidylinositol (PI)-3 kinase activity and led to increased (P < 0.001) phosphorylation of Akt on Ser(473) and Thr(308) in skeletal muscle. Interestingly, in response to prior exercise IRS-2-associated PI-3 kinase activity was higher (P < 0.05) both at basal and during insulin stimulation. This coincided with correspondingly altered phosphorylation of the extracellular-regulated protein kinase 1/2 (ERK 1/2), p70S6 kinase (P70S6K), eukaryotic elongation factor 2 (eEF2) kinase and eEF2. aPKC was similarly activated by insulin in rested and exercised muscle, without detectable changes in aPKC Thr(410) phosphorylation. However, when adding phosphatidylinositol-3,4,5-triphosphate (PIP3), the signalling product of PI-3 kinase, to basal muscle homogenates, aPKC was more potently activated (P = 0.01) in previously exercised muscle. Collectively, this study shows that endurance-type exercise interacts with insulin signalling to peptide chain elongation. Although protein turnover was not evaluated, this suggests that capacity for protein synthesis after acute endurance-type exercise may be improved. Furthermore, endurance exercise increased the responsiveness of aPKC to PIP3 providing a possible link to improved insulin-stimulated glucose uptake after exercise.

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Figures

Figure 1
Figure 1. Diagram showing insulin signalling through IRS-1 and IRS-2 to stimulate peptide chain elongation
Signalling through IRS-2 is suggested as an alternative pathway to signalling through IRS-1, allowing for exercise to interact with insulin signalling. Bold full circles show signalling improved by prior endurance exercise. Bold dashed circles show signalling not regulated by prior endurance exercise. Regular full circles show signalling components not investigated.
Figure 2
Figure 2. Schematic illustration of the experimental day
Grey areas indicate periods of either exercise (1 h) or insulin infusion (100 min). Arrows indicate time point of either muscle biopsies or blood sampling/venous blood flow measures.
Figure 3
Figure 3. Glucose uptake in the thigh measured using the Fick's principle
•, values in the rested leg. ○, values in the previously exercised leg. Insulin infusion is initiated at 0 min *P < 0.05 versus values in the rested leg. Values are means ±s.e.m., N = 12.
Figure 4
Figure 4. PI-3 kinase activity measured in muscle lysates
A, IRS-1-associated PI-3 kinase activity. B, IRS-2-associated PI-3 kinase activity. Filled bars are values in the rested leg. Open bars are values in the previously exercised leg. **P < 0.005 versus values in the rested leg, ††P < 0.005 versus basal values. Values are means ±s.e.m., N = 12.
Figure 5
Figure 5. Signalling to peptide chain elongation measured in muscle lysates using Western blotting
A, ERK1 (Thr202/Tyr204)/ERK2 (Thr185/Tyr187) phosphorylation. B, p70S6K (Thr389) phosphorylation. C, eEF2K (Ser366) phosphorylation. D, EF2 Thr56 phosphorylation. Filled bars are values in the rested (R) leg. Open bars are values in the previously exercised (Ex) leg. ††P < 0.005 versus basal values. **P < 0.005 versus values in the rested leg. *P < 0.05 versus values in the rested leg. Values are means ±s.e.m., N = 12.
Figure 6
Figure 6. aPKC Thr410 phosphorylation measured in muscle lysates using Western blotting
Filled bars are values in the rested (R) leg. Open bars are values in the previously exercised (Ex) leg. Values are means ±s.e.m., N = 12.
Figure 7
Figure 7. aPKC activity measured in vitro
A, aPKC activity in basal and insulin-stimulated samples. B, aPKC activity in basal samples, with or without addition of 10 μm PIP3. Filled bars are values in the rested leg. Open bars are values in the previously exercised leg. ††P < 0.005 versus basal values. †P < 0.05 versus basal values. *P < 0.05 versus response to PIP3 in the rested leg. Values are means ±s.e.m., N = 12.
Figure 8
Figure 8. Akt phosphorylation measured in muscle lysates using Western blotting
A, Akt Thr308 phosphorylation. B, Akt Ser473 phosphorylation. Filled bars are values in the rested (R) leg. Open bars are values in the previously exercised (Ex) leg. ††P < 0.005 versus basal values. Values are means ±s.e.m., N = 12.
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