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

Abstract:

: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-α (SIRP-α), 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-α expression was increased by a NF-κB-dependent pathway. Blockade of NF-κB using a small-molecule chemical inhibitor or a dominant-negative IKKβ reduced cytokine-induced SIRP-α expression. The overexpression of SIRP-α in myotubes impaired insulin signaling and raised proteolysis while SIRP-α 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-α is part of a novel mechanism for inflammation-mediated insulin resistance in muscle. In catabolic conditions with impaired insulin signaling, targeting SIRP-α may improve insulin sensitivity and prevent muscle atrophy.

journal_name

Kidney Int

journal_title

Kidney international

authors

Thomas SS,Dong Y,Zhang L,Mitch WE

doi

10.1038/ki.2013.97

subject

Has Abstract

pub_date

2013-08-01 00:00:00

pages

308-16

issue

2

eissn

0085-2538

issn

1523-1755

pii

S0085-2538(15)55975-9

journal_volume

84

pub_type

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