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1 Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois, United States
2 Physiology & Biophysics, University of Illinois at Chicago, Chicago, Illinois, United States; Preventive Medicine, Northwestern University, 680 N. Lake Shore Dr., CHicago, Illinois, 60611, United States
3 Cardiology Secton, M/C 787, University of Illinois at Chicago, Chicago, Illinois, United States
4 Hospital of the University of Pennsylvania, University of Pennsylvania, Philadelphia, Pennsylvania, United States
5 Cardiovascular Institute, Loyola University, Maywood, Illinois, United States
6 Medicine, UCSD, La Jolla, California, United States
7 Dept. of Physiology & Biophysics, Univ. of Illinois at Chicago, Chicago, Illinois, United States
8 Department of Physiology and Biophysics, UIC, Chicago, Illinois, United States
* To whom correspondence should be addressed. E-mail: russell{at}uic.edu.
Prolonged hemodynamic overload results in cardiac hypertrophy and failure with detrimental changes in myocardial gene expression and morphology. CSRP3 or muscle LIM protein (MLP) is thought to be a mechanosensor in cardiac myocytes. Therefore, the subcellular location of MLP may have functional implications in health and disease. Our hypothesis is that MLP becomes mislocalized after prolonged overload resulting in impaired mechanosensing in cardiac myocytes. Using the techniques of biochemical subcellular fractionation and immunocytochemistry, we found MLP exhibits oligomerization in the membrane and cytoskeleton of cultured cardiac rat neonatal myocytes. Nuclear MLP was always monomeric. MLP translocated to the nucleolus in response to 10% cyclic stretch at 1Hz for 48 hours. This was associated with a 3 fold increase in S6 ribosomal protein (p<0.01 n=3 cultures). Adenoviral over-expression of MLP also resulted in a 2 fold increase in S6 protein suggesting that MLP can activate ribosomal protein synthesis in the nucleolus. In ventricles from aortic banded and myocardial infarcted rat hearts, nuclear MLP increased by 2 fold (p<0.01 n=7) along with a significant decrease in the non-nuclear oligomeric fraction. The ratio of nuclear to non-nuclear MLP increased 3 fold in both groups (p<0.01 n=7). In failing human hearts there was almost a complete loss of oligomeric MLP. Using a flag-tagged adenoviral MLP, we demonstrate that the C-terminus is required for oligomerization and that this is a precursor to stretch sensing and subsequent nuclear translocation. Therefore, reduced oligomeric MLP in the costamere and cytoskeleton may contribute to impaired mechanosensing in heart failure.
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