Hypertrophic growth in cardiac myocytes is mediated by Myc through a Cyclin D2-dependent pathway

Abstract

c‐Myc (Myc) is highly expressed in developing embryos where it regulates body size by controlling proliferation but not cell size. However, Myc is also induced in many postmitotic tissues, including adult myocardium, in response to stress where the predominant form of growth is an increase in cell size (hypertrophy) and not number. The function of Myc induction in this setting is unproven. Therefore, to explore Myc's role in hypertrophic growth, we created mice where Myc can be inducibly inactivated, specifically in adult myocardium. Myc‐deficient hearts demonstrated attenuated stress‐induced hypertrophic growth, secondary to a reduction in cell growth of individual myocytes. To explore the dependence of Myc‐induced cell growth on CycD2, we created bigenic mice where Myc can be selectively activated in CycD2‐null adult myocardium. Myc‐dependent hypertrophic growth and cell cycle reentry is blocked in CycD2‐deficient hearts. However, in contrast to Myc‐induced DNA synthesis, hypertrophic growth is independent of CycD2‐induced Cdk2 activity. These data suggest that Myc is required for a normal hypertrophic response and that its growth‐promoting effects are also mediated through a CycD2‐dependent pathway.

Myc controls transcriptional regulation of cardiac metabolism and mitochondrial biogenesis in response to pathological stress in mice

“…Myc is not expressed in the adult heart under normal physiological conditions; however, it is upregulated rapidly in response to virtually all forms of pathologic stress (17,18). Although work by our group and others has demonstrated that Myc is required for hypertrophic growth after hemodynamic stress (19)(20)(21), its role in regulating metabolism and mitochondrial biogenesis in the heart is unknown.…”

“…To evaluate whether Myc was required for the increased expression of genes involved in glucose metabolism typically seen after hypertrophic stimuli, we examined Myc-deficient mice in which Myc can be inducibly inactivated, specifically in adult myocardium with a tamoxifen-regulated Cre (21). Deletion of Myc attenuates hypertrophic growth in response to both hemodynamic and pharmacologic hypertrophic stimuli (21).…”

p53 regulates the cardiac transcriptome

“…Studies in animal models have linked several master TFs (Gata4, c-Myc, Nfat3, NF-κB) to the induction of pathological gene sets that leads to the development of HF (14,(29)(30)(31). Moreover, physical exercise also highly influences cardiac function through increases in expression of these specific gene sets (32).…”

Integration of Insulin receptor/Foxo signaling and dMyc activity during muscle growth regulates body size inDrosophila

“…Directly relevant to our studies, both MYC and InR (INSR) signaling have been found to regulate muscle growth and maintenance in humans (Sandri et al, 2004;Southgate et al, 2007;Stitt et al, 2004;Zhong et al, 2006). Further, muscle atrophy is triggered by FOXO activation in several pathological conditions (Glass, 2003b;Sandri et al, 2004;Stitt et al, 2004).…”

“…Further, muscle atrophy is triggered by FOXO activation in several pathological conditions (Glass, 2003b;Sandri et al, 2004;Stitt et al, 2004). In addition, MYC function has been implicated in heart hypertrophy (Bello Roufai et al, 2007;Xiao et al, 2001;Zhong et al, 2006), a process that is conversely regulated by FOXO (Evans-Anderson et al, 2008;Skurk et al, 2005).…”