© 1996 American Heart Association, Inc.
Articles |
Cardiomyopathy in Transgenic myf5 Mice
From the Department of Microbiology and Immunology (J.G.E., L.A.L.), the Department of Medicine (A.M.), and the Department of Pathology (S.F.), Albert Einstein College of Medicine, Bronx, NY, and the Department of Anatomy (G.E.L., B.K.M.), University of Wisconsin Medical School, Madison.
Correspondence to L.A. Leinwand, Professor and Chair, MCDB CB 347, University of Colorado, Boulder, CO 80309-0347. E-mail leinwand@beagle.colorado.edu.
Abstract To explore the compatibility of skeletal and cardiac
programs of gene expression, transgenic mice that express a skeletal
muscle myogenic regulator, bmyf5, in the heart were
analyzed. These mice develop a severe
cardiomyopathy and exhibit a significantly shorter
life span than do their nontransgenic littermates. The transgene was
expressed from day 7.5 post coitum forward, resulting in activation of
skeletal muscle genes not normally seen in the myocardium.
Cardiac pathology was not apparent at midgestation but was evident by
day 2 of postnatal life, and by 42 days, hearts exhibited multifocal
interstitial inflammation, fibrosis, cellular
hypertrophy, and occasional myocyte degeneration. All four
chambers of the heart were enlarged to varying degrees, with the atria
demonstrating the most significant hypertrophy (>100% in
42-day-old mice). The transgene and several skeletal
muscle–specific genes were expressed only in patchy areas of the
heart in heterozygous mice. However, molecular markers of
hypertrophy (such as 
-skeletal actin and atrial
myosin light chain-1) were expressed with a wider distribution,
suggesting that their induction was secondary to the expression of the
transgene. In older (28-week-old) mice, lung weights were also
significantly increased, consistent with congestive heart
failure. The life span of bmyf5 mice was significantly
shortened, with an average life span of 109 days, compared with at
least a twofold longer life expectancy for nontransgenic littermates.
Expression of the transgene was associated with an increase in
Ca2+-stimulated myofibrillar ATPase in myofibrils obtained
from the left ventricles of 42-day-old bmyf5 mice.
Myocardial bmyf5 expression therefore induces a program of
skeletal muscle gene expression that results in progressive
cardiomyopathy that may be due to incompatibility
of heart and skeletal muscle structural proteins.
Key Words: cardiomyopathy • bmyf5 • transgenic mice • hypertrophy
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