FB, Davis PJ. Thyroid hormone inhibition in L6 myoblasts of IGF-Imediated glucose uptake and proliferation: new roles for integrin ␣v3. Am J Physiol Cell Physiol 307: C150-C161, 2014. First published May 7, 2014 doi:10.1152/ajpcell.00308.2013.-Thyroid hormones L-thyroxine (T4) and 3,3=,5-triiodo-L-thyronine (T3) have been shown to initiate shortand long-term effects via a plasma membrane receptor site located on integrin ␣v3. Also insulin-like growth factor type I (IGF-I) activity is known to be subject to regulation by this integrin. To investigate the possible cross-talk between T4 and IGF-I in rat L6 myoblasts, we have examined integrin ␣v3-mediated modulatory actions of T4 on glucose uptake, measured through carrier-mediated 2-deoxy-[3 H]-D-glucose uptake, and on cell proliferation stimulated by IGF-I, assessed by cell counting, [3 H]-thymidine incorporation, and fluorescence-activated cell sorting analysis. IGF-I stimulated glucose transport and cell proliferation via the cell surface IGF-I receptor (IGFIR) and, downstream of the receptor, by the phosphatidylinositol 3-kinase signal transduction pathway. Addition of 0.1 nM free T4 caused little or no cell proliferation but prevented both glucose uptake and proliferative actions of IGF-I. These actions of T4 were mediated by an Arg-GlyAsp (RGD)-sensitive pathway, suggesting the existence of crosstalk between IGFIR and the T4 receptor located near the RGD recognition site on the integrin. An RGD-sequence-containing integrin inhibitor, a monoclonal antibody to ␣v3, and the T4 metabolite tetraiodothyroacetic acid all blocked the inhibition by T4 of IGF-I-stimulated glucose uptake and cell proliferation. Western blotting confirmed roles for activated phosphatidylinositol 3-kinase and extracellular regulated kinase 1/2 (ERK1/2) in the effects of IGF-I and also showed a role for ERK1/2 in the actions of T4 that modified the effects of IGF-I. We conclude that thyroid hormone inhibits IGF-I-stimulated glucose uptake and cell proliferation in L6 myoblasts. glucose transport; insulin-like growth factor type I; fluorescenceactivated cell sorting; tetraiodothyroacetic acid; thyroxine; triiodothyronine; mitogen-activated protein kinase; extracellular regulated kinase 1/2; phosphatidylinositol 3-kinase