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PNAS 97 (1): 38-43

Copyright © 2000 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / APPLIED BIOLOGICAL SCIENCES

Exercise-induced changes in expression and activity of proteins involved in insulin signal transduction in skeletal muscle: Differential effects on insulin-receptor substrates 1 and 2

Alexander V. Chibalin, Mei Yu, Jeffrey W. Ryder, Xiao Mei Song, Dana Galuska, Anna Krook, Harriet Wallberg-Henriksson, and Juleen R. Zierath*

Department of Surgical Sciences, Karolinska Hospital, S-171 76, and the Department of Physiology and Pharmacology, Karolinska Institutet, S-171 77, Stockholm, Sweden

Accepted for publication November 18, 1999.

Received for publication April 1, 1999.

Abstract: Level of physical activity is linked to improved glucose homeostasis. We determined whether exercise alters the expression and/or activity of proteins involved in insulin-signal transduction in skeletal muscle. Wistar rats swam 6 h per day for 1 or 5 days. Epitrochlearis muscles were excised 16 h after the last exercise bout, and were incubated with or without insulin (120 nM). Insulin-stimulated glucose transport increased 30% and 50% after 1 and 5 days of exercise, respectively. Glycogen content increased 2- and 4-fold after 1 and 5 days of exercise, with no change in glycogen synthase expression. Protein expression of the glucose transporter GLUT4 and the insulin receptor increased 2-fold after 1 day, with no further change after 5 days of exercise. Insulin-stimulated receptor tyrosine phosphorylation increased 2-fold after 5 days of exercise. Insulin-stimulated tyrosine phosphorylation of insulin-receptor substrate (IRS) 1 and associated phosphatidylinositol (PI) 3-kinase activity increased 2.5- and 3.5-fold after 1 and 5 days of exercise, despite reduced (50%) IRS-1 protein content after 5 days of exercise. After 1 day of exercise, IRS-2 protein expression increased 2.6-fold and basal and insulin-stimulated IRS-2 associated PI 3-kinase activity increased 2.8-fold and 9-fold, respectively. In contrast to IRS-1, IRS-2 expression and associated PI 3-kinase activity normalized to sedentary levels after 5 days of exercise. Insulin-stimulated Akt phosphorylation increased 5-fold after 5 days of exercise. In conclusion, increased insulin-stimulated glucose transport after exercise is not limited to increased GLUT4 expression. Exercise leads to increased expression and function of several proteins involved in insulin-signal transduction. Furthermore, the differential response of IRS-1 and IRS-2 to exercise suggests that these molecules have specialized, rather than redundant, roles in insulin signaling in skeletal muscle.

* To whom reprint requests should be addressed at: Department of Clinical Physiology, Karolinska Hospital, SE-171 76 Stockholm, Sweden. E-mail: jrz{at}klinfys.ks.se.

Communicated by Vernon R. Young, Massachusetts Institute of Technology, Cambridge, MA

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