The c-myc Proto-Oncogene Regulates Cardiac Development in Transgenic Mice

Abstract

During the maturation of the cardiac myocyte, a transition occurs from hyperplastic to hypertrophic growth. The factors that control this transition in the developing heart are unknown. Proto-oncogenes such as c-myc have been implicated in the regulation of cellular proliferation and differentiation, and in the heart the switch from myocyte proliferation to terminal differentiation is synchronous with a decrease in c-myc mRNA abundance. To determine whether c-myc can influence myocyte proliferation or differentiation, we examined the in vivo effect of increasing c-myc expression during embryogenesis and of preventing the decrease in c-myc mRNA expression that normally occurs during cardiac development. The model system used was a strain of transgenic mice exhibiting constitutive expression of c-myc mRNA in cardiac myocytes throughout development. In these transgenic mice, increased c-myc mRNA expression was found to be associated with both atrial and ventricular enlargement. This increase in cardiac mass was secondary to myocyte hyperplasia, with the transgenic hearts containing more than twice as many myocytes as did nontransgenic hearts. The results suggest that in the transgenic animals there is additional hyperplastic growth during fetal development. However, this additional proliferative growth is not reflected in abnormal myocyte maturation, as assessed by the expression of the cardiac and skeletal isoforms of alpha-actin. The results of this study indicate that constitutive expression of c-myc mRNA in the heart during development results in enhanced hyperplastic growth and suggest a regulatory role for this proto-oncogene in cardiac myogenesis.

The MRE11-NBS1-RAD50 pathway is perturbed in SV40 large T antigen-immortalized AT-1, AT-2 and HL-1 cardiomyocytes

“…However, mammalian cardiomyocyte proliferation has been induced by the expression of the SV40 large T antigen (T-ag) oncoprotein, as shown in transgenic mice (7)(8)(9), cultured neonatal rat cardiomyocytes (10,11) and human fetal cardiomyocytes (12). In transgenic mice, cardiomyocyte proliferation was also induced by the expression of c-MYC (13), calmodulin (14) and insulin-like growth factor-1 (15). These examples of induced cardiomyocyte proliferation support the possibility of stimulating cardiac myocyte proliferation in vivo subsequent to cardiac trauma as a means of replacing lost functional cardiac tissue.…”

Cardiomyocyte Proliferation from Fetal- to Adult- and from Normal- to Hypertrophy and Failing Hearts

“…In an attempt to unravel the myriad of possibilities that control the conversion from fetal hyperplastic growth to post-natal hypertrophically growing CMs that no longer are able to divide, many experimental studies have been published. Experimental interventions include genetically altered animals [ 92 , 93 , 94 , 95 ], fetal or early neonatal hypoxia [ 96 , 97 , 98 , 99 , 100 ], anemia [ 101 , 102 ], manipulations of metabolic or growth regulators [ 103 , 104 , 105 , 106 ], pressure, and volume overloads [ 107 , 108 ], and others. In general, experimental interventions during fetal or early neonatal growth tend to accelerate hyperplasia and alter the onset of hypertrophic growth.…”

“…In a transgenic mouse with overexpression of the c-myc oncogene, the transgenic mice underwent one additional CM division during the fetal period. The transgenic mice had a 50–100% increase in P1 heart weight because of twice the number of CMs with little change in body weight compared to wild-type littermates [ 92 , 93 , 94 ]. In addition to the doubling of CM number during the fetal period, conversion to hypertrophic growth and binucleation began at P3 in the transgenic mice vs. P7 in the wild-type littermates, suggesting that the number of myocyte divisions may have some intrinsic control.…”

“…In an adult tamoxifen-inducible myc transgenic mouse, myc activation-induced nuclear mitosis and a 41% increase in cardiac mass due to hypertrophy of the CMs [ 112 ], illustrating the differing effects of a stimulator on replicating vs. non-replicating CMs. Interestingly, in the c-myc transgenic mice which continued to express c-myc in adult mice, heart mass was greater than in wild-type due to increased cell number, but not due to increased cell size [ 92 , 93 , 94 ].…”

Identifying metabolic adaptations during cardiotoxicity using paired transcriptomics and metabolomics data integrated with a model of heart metabolism

“…The second principal component separates between the 6-hour and 24-hour samples, including the control samples, suggesting a potential adaptation to culture conditions. A gene enrichment analysis for the top 100 genes in the second principal component identifies Myc targets as uniquely enriched, where consistent decreased expression of the Myc pathways is consistent with a transition from the fetal gene program (Jackson et al, 1990) and increased expression consistent with a response to cardiomyocyte stress (Lee et al, 2009;Ahuja et al, 2010).…”