In adipocytes, the Cbl/CAP dependent signaling pathway has been involved in regulating insulin-stimulated glucose uptake. We investigated activation of Cbl and its downstream effector TC10 in cardiac and skeletal muscle of Balb/C mice. Insulin administration resulted in Cbl phosphorylation in cardiac, skeletal muscle, and adipose tissue. Subsequent TC10 activation was detected only in heart and adipose tissue. c-Cbl and CAP gene expression was significantly reduced in the heart tissue of streptozotocin-induced diabetic animals, whereas no change was observed for other components of the pathway. No changes in Cbl expression were detected in hindlimb muscle. In leptin(-/-) obese mice Cbl expression in heart and adipose tissue was maintained, although insulin-mediated Cbl phosphorylation and subsequent TC10 activation were significantly reduced. In conclusion, Our data demonstrate that Cbl/CAP/TC10 insulin signaling pathway is active in cardiac muscle and impaired during obesity and insulin deficiency. (c) 2006 Elsevier Inc. All rights reserved.