Published online before print July 28, 2005, doi: 10.1161/01.RES.0000179580.72375.c2
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Submitted on January 28, 2005
Revised on June 22, 2005
Accepted on July 19, 2005
Transgenic Overexpression of Locally Acting Insulin-Like Growth Factor-1 Inhibits Ubiquitin-Mediated Muscle Atrophy in Chronic Left-Ventricular Dysfunction
P. Christian Schulze *;
From the Cardiovascular Research (P.C.S., J.F., K.A.K., J.G., M.C., C.M., R.T.L.), Brigham and Women’s Hospital, Harvard Medical School, Partners Research Facility, Cambridge, Mass; and Mouse Biology Programme (N.R.), European Molecular Biology Laboratory, Monterotondo/Rome, Italy.
* To whom correspondence should be addressed. E-mail: pcschulze{at}rics.bwh.harvard.edu.
Metabolic abnormalities develop in various chronic diseases and lead to progressive catabolism with decrements in the skeletal musculature that result in muscle atrophy. We investigated pathways of skeletal muscle proteolysis using an experimental model of chronic left-ventricular dysfunction. Skeletal muscle atrophy developed in wild-type mice 12 weeks following myocardial infarction accompanied by an increase in total protein ubiquitination and enhanced proteasome activity, activation of Foxo transcription factors, and robust induction of the ubiquitin-protein ligase atrogin-1/MAFbx. Further studies identified skeletal muscle myosin as a specific target of ubiquitin-mediated degradation in muscle atrophy. In contrast, transgenic overexpression of a local isoform of insulin-like growth factor-1 prevented muscle atrophy and increased proteasome activity, inhibited skeletal muscle activation primarily of Foxo4, and blocked the expression of atrogin-1/MAFbx. These results suggest that skeletal muscle atrophy occurs through increased activity of the ubiquitin-proteasome pathway. The inhibition of muscle atrophy by local insulin-like growth factor-1 provides a promising therapeutic avenue for the prevention of skeletal muscle wasting in chronic heart failure and potentially other chronic diseases associated with skeletal muscle atrophy.
Key words: insulin-like growth-1 • chronic heart failure • skeletal muscle • atrophy • gene expression
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