Cardiomyopathy in transgenic myf5 mice.
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 alpha-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.
Edwards
J G
JG
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA.
Lyons
G E
GE
Micales
B K
BK
Malhotra
A
A
Factor
S
S
Leinwand
L A
LA
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D009202:Cardiomyopathies / Q000196:embryology / Q000235:genetics* / Q000473:pathology; D004268:DNA-Binding Proteins; D005318:Fetal Heart / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D015870:Gene Expression; D017403:In Situ Hybridization; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000235:genetics*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D051787:Myogenic Regulatory Factor 5; D018006:Myogenic Regulatory Factors / Q000235:genetics*; D009929:Organ Size; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics*; D019076:Transgenes
D004268:DNA-Binding Proteins; D009124:Muscle Proteins; C497418:Myf5 protein, mouse; D051787:Myogenic Regulatory Factor 5; D018006:Myogenic Regulatory Factors; D015534:Trans-Activators; D014157:Transcription Factors