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Insulin Receptor Substrate-4 Is Expressed in Muscle Tissue without Acting as a Substrate for the Insulin Receptor

Molecular Cardiology (S.S., D.L., I.R., J.E.), Department of Clinical Biochemistry and Pathobiochemistry, German Diabetes Research Institute, D-40225 Düsseldorf, Germany; and Institute of Pathophysiology (I.K.), University of Greifswald, D-17495 Karlsburg, Germany

Address all correspondence and requests for reprints to: Professor Dr. Jürgen Eckel, German Diabetes Research Institute, Auf’m Hennekamp 65, D-40225 Düsseldorf, Germany. E-mail: eckel{at}uni-duesseldorf.de.

Insulin receptor substrate (IRS) proteins represent key elements of the insulin-signaling cascade. IRS-4 is the most recently characterized member of the IRS family with an undefined in vivo function. In contrast to IRS-1 and IRS-2, IRS-4 exhibits a limited tissue expression, and IRS-4 protein has not been detected in any mouse or primary human tissue so far. The purpose of the present study was to analyze the expression of IRS-4 in rat muscle and human skeletal muscle cells and assess involvement of IRS-4 in initial insulin signaling. Using immunoblotting and immunoprecipitation, the specific expression of IRS-4 protein could be demonstrated in rat soleus and cardiac muscle and human skeletal muscle cells, but it was not significantly detectable in quadriceps and gastrocnemius. A prominent down-regulation of IRS-4 was observed in heart and soleus muscle of WOKW rats, an animal model of the metabolic syndrome. In human skeletal muscle cells, both IRS-1 and IRS-2 are rapidly phosphorylated on tyrosine in response to insulin, whereas essentially no tyrosine phosphorylation of IRS-4 was observed in response to both insulin and IGF-I. Instead, a 2-fold increase in IRS-4 tyrosine phosphorylation was observed in myocytes subjected to osmotic stress. In conclusion, IRS-4 protein is expressed in heart and skeletal muscle in a fiber type specific fashion. Our data suggest that IRS-4 does not function as a substrate of the insulin and the IGF-I receptor in primary muscle cells but may be involved in nonreceptor tyrosine kinase signaling.

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