Signal regulatory protein-α interacts with the insulin receptor contributing to muscle wasting in chronic kidney disease

Insulin resistance from chronic kidney disease (CKD) stimulates muscle protein wasting but mechanisms causing this resistance are controversial. To help resolve this, we used microarray analyses to identify initiators of insulin resistance in the muscles of mice with CKD, glucose intolerance, and insulin resistance. CKD raised mRNAs of inflammatory cytokines in muscles and there was a 5.2-fold increase in signal regulatory protein-alpha (SIRP-alpha), a transmembrane glycoprotein principally present in muscle membranes. By immunoprecipitation we found it interacts with the insulin receptor and insulin receptor substrate-1 (IRS-1). Treatment of myotubes with a mixture of inflammatory cytokines showed that SIRP-alpha expression was increased by a NF-kappa B-dependent pathway. Blockade of NF-kappa B using a small-molecule chemical inhibitor or a dominant-negative IKK beta reduced cytokine-induced SIRP-alpha expression. The overexpression of SIRP-alpha in myotubes impaired insulin signaling and raised proteolysis while SIRP-alpha knockdown with siRNAs in skeletal muscle cells increased tyrosine phosphorylation of the insulin receptor and IRS-1 despite inclusion of cytokines. This led to increased p-Akt and suppression of protein degradation. Thus, SIRP-alpha is part of a novel mechanism for inflammation-mediated insulin resistance in muscle. In catabolic conditions with impaired insulin signaling, targeting SIRP-alpha may improve insulin sensitivity and prevent muscle atrophy.