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 re gulator, bmyf5, in the heart were analyzed. These mice develop a sever e 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 g enes not normally seen in the myocardium. Cardiac pathology was not ap parent at midgestation but was evident by day 2 of postnatal life, and by 42 days, hearts exhibited multifocal interstitial inflammation, fi brosis, 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 w ere expressed only in patchy areas of the heart in heterozygous mice. However, molecular markers of hypertrophy (such as alpha-skeletal acti n and atrial myosin light chain-1) were expressed with a wider distrib ution, 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. Th e life span of bmyf5 mice was significantly shortened, with an average life span of 109 days, compared with at least a twofold longer life e xpectancy for nontransgenic littermates. Expression of the transgene w as associated with an increase in Ca2+-stimulated myofibrillar ATPase in myofibrils obtained from the left ventricles of 42-day-old bmyf5 mi ce. Myocardial bmyf5 expression therefore induces a program of skeleta l muscle gene expression that results in progressive cardiomyopathy th at may be due to incompatibility of heart and skeletal muscle structur al proteins.