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Am J Physiol Endocrinol Metab 292: E292-E297, 2007. First published September 19, 2006; doi:10.1152/ajpendo.00189.2006
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Regulation of IGF-I receptor signaling in diabetic cardiac muscle: dysregulation of cytosolic and mitochondria HSP60

¹Center for Diabetes Research and Treatment and Department of Medicine, University of California, Irvine, California; ²Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, and Taichung Veterans General Hospital, Taichung, Taiwan; ³Department of Physiology and Biophysics; and ⁴Department of Biological Chemistry, University of California, Irvine, California

Submitted 19 April 2006 ; accepted in final form 5 September 2006

Insulin deficiency downregulates HSP60 and IGF-I receptor signaling and disrupts intracellular signaling homeostasis in diabetic cardiac muscle. Our previous studies had shown that IGF-I receptor signaling can be modulated by the abundance of HSP60. Since HSP60 localizes to the cytoplasmic compartment and mitochondria, this study was carried out to determine the distribution of cytosolic and mitochondria HSP60 in diabetic myocardium and to explore whether cytosolic HSP60 can modulate IGF-I receptor signaling in cardiac muscle cells. In streptozotocin-induced diabetes, both the cytosolic and mitochondrial fractions of HSP60 were decreased in the myocardium. Incubating primary cardiomyocytes with insulin leads to increased abundance of HSP60 in the cytosolic and mitochondria compartments. To determine whether cytosolic HSP60 can modulate IGF-I receptor signaling, we used rhodamine 6G to deplete functional mitochondria in cardiomyocytes. In the mitochondria-depleted cells, overexpression of HSP60 with adenoviral vector increased the abundance of IGF-I receptor, enhanced IGF-I-activated receptor phosphorylation, and augmented IGF-I activation of Akt and ERK. Thus overexpressing HSP60 in the cytosolic compartment enhanced IGF-I receptor signaling through upregulation of IGF-I receptor protein. However, IGF-I receptor signaling was significantly reduced in the mitochondria-depleted cells, which suggested that maintaining normal IGF-I receptor signaling in cardiomyocytes required functioning mitochondria. The effect of cytosolic HSP60 involved suppression of ubiquitin conjugation to IGF-I receptor in cardiomyocytes. These data suggest two different mechanisms that can regulate IGF-I signaling, one via cytosolic HSP60 suppression of IGF-I receptor ubiquitination and the other via mitochondria modulation. These findings provide new insight into the regulation of IGF-I signaling in diabetic cardiomyopathy.

insulin receptor; Akt; ubiquitin; insulin-like growth factor I; heat shock protein-60