Cell Cycle Re-Entry and Mitochondrial Defects in Myc-Mediated Hypertrophic Cardiomyopathy and Heart Failure

Abstract

While considerable evidence supports the causal relationship between increases in c-Myc (Myc) and cardiomyopathy as a part of a “fetal re-expression” pattern, the functional role of Myc in mechanisms of cardiomyopathy remains unclear. To address this, we developed a bitransgenic mouse that inducibly expresses Myc under the control of the cardiomyocyte-specific MHC promoter. In adult mice the induction of Myc expression in cardiomyocytes in the heart led to the development of severe hypertrophic cardiomyopathy followed by ventricular dysfunction and ultimately death from congestive heart failure. Mechanistically, following Myc activation, cell cycle markers and other indices of DNA replication were significantly increased suggesting that cell cycle-related events might be a primary mechanism of cardiac dysfunction. Furthermore, pathological alterations at the cellular level included alterations in mitochondrial function with dysregulation of mitochondrial biogenesis and defects in electron transport chain complexes I and III. These data are consistent with the known role of Myc in several different pathways including cell cycle activation, mitochondrial proliferation, and apoptosis, and indicate that Myc activation in cardiomyocytes is an important regulator of downstream pathological sequelae. Moreover, our findings indicate that the induction of Myc in cardiomyocytes is sufficient to cause cardiomyopathy and heart failure, and that sustained induction of Myc, leading to cell cycle re-entry in adult cardiomyocytes, represents a maladaptive response for the mature heart.

Cardiac muscle regeneration: lessons from development

“…In many instances, persistent cycling of cardiomyocytes has been associated with concurrent apoptosis, defective differentiation, and lethal heart failure; e.g., after combined deletion of Rb plus p130 (MacLellan et al 2005), forced expression of Myc (Lee et al 2009), or combined deletion of miR-133a-1 and miR-133a-2 (Liu et al 2008). This might not be the obligatory consequence of cycling itself, but rather a reflection of specific genes' dual roles in growth and differentiation.…”

Identify potential chronic heart failure related transcription factors by network analysis

“…Results showed that the induction of MYC expression in cardiomyocytes led to the development of severe hypertrophic cardiomyopathy followed by ventricular dysfunction and ultimately death from congestive heart failure. MYC activation in cardiomyocytes is an important regulator of downstream pathological sequelae (Lee et al, 2009).…”

Exercise tames the wild side of the Myc network: a hypothesis

“…The Myc network has been studied extensively in cancer cells and may account for the Warburg effect, which fuels the survival and proliferation of cancer cells (46,47,49,50,77,185,215) by activating glycolysis and mitochondrial metabolism. Furthermore, c-Myc also appears to transduce ER-Ca ϩϩ signals (possibly relevant to excitation-contraction coupling in muscle) and affect mitochondrial functions (220) and mitochondrial biogenesis, independent of PGC-1␣, in cardiac muscle (122). Equally relevant to control of glycemia by exercise is the observation that Myc may also transduce insulin signals (193).…”

“…Several genes encoding the glycolytic enzymes have the canonical E-box in their promoters (109). The contribution of the Myc network on the expression of the mitochondrial electron transport chain and mitochondrial biogenesis, possibly independent of PGC-1␣, has been described in the cardiac muscle (1,122). Bioinformatic network analysis of exercise-sensitive transcriptome of human muscles identified Myc to be a "hot spot" that connects changes in multiple transcripts (106).…”

“…It also shows that some of the effects of Myc on glycolysis are also subject to regulation by hypoxia-inducible factor-1 (HIF-1) (48). The possible contribution of the Myc network in mitochondrial biogenesis is also indicated from several investigations (1,49,51,63,167) that included studies in cardiac muscle (1,122). Less appreciated is the induction of HKII, a rate-controlling enzyme of glycolysis and a Myc network target gene, by exercise (118,162) and its possible localization to mitochondria after exercise (202).…”