Submitted on April 19, 2006
Accepted on September 5, 2006
Regulation of IGF-1 Receptor Signaling in Diabetic Cardiac Muscle: Dysregulation of Cytosolic and Mitochondria Hsp60
Hui-Chin Lai1, Tsun-Jui Liu1, Chih-Tai Ting2, Jia-Ying Yang1, Lan Huang3, Douglas Wallace4, Peter Kaiser4, and Ping H Wang5*
1 Medicine, University of California Irvine, Irvine, California, United States
2 Cardiology, Veterans General Hospital, Taichung, Taiwan - Republic of China
3 Physiology and Biophysics, University of California Irvine, Irvine, California, United States
4 Biological Chemistry, University of California Irvine, Irvine, California, United States
5 Medicine, University of California Irvine, Irvine, California, United States; Medicine, University of California-Irvine, 46 Urey Ct., Irvine, California, 92697, United States
* To whom correspondence should be addressed. E-mail: phwang{at}uci.edu.
Insulin deficiency down-regulates HSP60 and IGF-1 receptor signaling and disrupts intracellular signaling homeostasis in diabetic cardiac muscle. Our previous studies had shown that IGF-1 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-1 receptor signaling in cardiac muscle cells. In streptozotocin-induced diabetes, the cytosolic and mitochondrial fractions of HSP60 were both decreased in the myocardium. Incubating primary cardiomyocytes with insulin lead to increased abundance of HSP60 in the cytosolic and mitochondria compartments. To determine whether cytosolic HSP60 can modulate IGF-1 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-1 receptor, enhanced IGF-1 activated receptor phosphorylation, and augmented IGF-1 activation of Akt and Erk. Thus, overexpressing HSP60 in the cytosolic compartment enhanced IGF-1 receptor signaling through up-regulation of IGF-1 receptor protein. However, IGF-1 receptor signaling was significantly reduced in the mitochondria-depleted cells, which suggested that maintaining normal IGF-1 receptor signaling in cardiomyocytes required functioning mitochondria. The effect of cytosolic HSP60 involved suppression of ubiquitin conjugation to IGF-1 receptor in cardiomyocytes. These data suggest two different mechanisms that can regulate IGF-1 signaling, via cytosolic HSP60 suppression of IGF-1 receptor ubiquitination and via mitochondria modulation. These findings provide new insight into the regulation of IGF-1 signaling in diabetic cardiomyopathy.
