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Cell cycle re-entry and mitochondrial defects in myc-mediated hypertrophic cardiomyopathy and heart failure.

Lee HG, Chen Q, Wolfram JA, Richardson SL, Liner A, Siedlak SL, Zhu X, Ziats NP, Fujioka H, Felsher DW, Castellani RJ, Valencik ML, McDonald JA, Hoit BD, Lesnefsky EJ, Smith MA - PLoS ONE (2009)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States of America. hyoung-gon.lee@case.edu

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.

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Related in: MedlinePlus

The expression of Myc leads to a decreased rate of dinitrophenol uncoupled respiration when glutamate+malate and succinate+rotenone were used as complex I and complex II substrates compared to the mitochondria from Myc-OFF or single transgenic mice (Single Tg) (Panel A).Myc did not affect the oxidation of TMPD-ascorbate (Panel A). Direct measurement of electron transport chain enzyme activity shows that Myc decreased activities of complex I, NCR (NADH cytochrome c oxidoreductase), and complex III (Panel B). Data are expressed as mean±SEM; * p<0.05 vs. Myc-OFF and Single Tg. n = 5 for Myc-ON and Myc-OFF, and n = 4 for Single Tg.
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pone-0007172-g008: The expression of Myc leads to a decreased rate of dinitrophenol uncoupled respiration when glutamate+malate and succinate+rotenone were used as complex I and complex II substrates compared to the mitochondria from Myc-OFF or single transgenic mice (Single Tg) (Panel A).Myc did not affect the oxidation of TMPD-ascorbate (Panel A). Direct measurement of electron transport chain enzyme activity shows that Myc decreased activities of complex I, NCR (NADH cytochrome c oxidoreductase), and complex III (Panel B). Data are expressed as mean±SEM; * p<0.05 vs. Myc-OFF and Single Tg. n = 5 for Myc-ON and Myc-OFF, and n = 4 for Single Tg.

Mentions: Based on our ultrastructural findings, and since defects in mitochondrial metabolism contribute to the pathogenesis and progression of heart failure, we explored whether functional deficits in mitochondrial metabolism were associated with the observed changes in size and number of mitochondria in Myc-ON mice. Myc-ON expression led to a decrease in protein yield of mitochondria compared to the Myc-OFF or single transgenic mice (Table 2). Moreover, the specific activity of citrate synthase, a mitochondrial marker enzyme, was decreased in the mitochondria from Myc-ON mice compared to the mitochondria from Myc-OFF or single transgenic mice (Myc-ON 3540±160* mU/mg protein, n = 5 , p<0.05 vs. both Myc-OFF 4159±144, n = 5, and Single Tg 4105±156, n = 4). With glutamate plus malate as the donor of reducing equivalents to complex I, the rate of state 3 respiration was lower in Myc-ON compared to the Myc-OFF or single transgenic mice and state 4 respiration was also decreased in Myc-ON mitochondria compared to other groups. In contrast, the respiratory control ratio (RCR, state3/state4) was higher in Myc-ON mouse mitochondria compared to the Myc-OFF or single groups and there was no difference in the ADP/O ratio among groups (Table 2). With succinate plus rotenone as the complex II substrate, respiration was also decreased in Myc-ON mitochondria. The decreased oxidation in the presence of dinitrophenol localizes the defect to the mitochondrial electron transport chain (Table 2, Figure 8).


Cell cycle re-entry and mitochondrial defects in myc-mediated hypertrophic cardiomyopathy and heart failure.

Lee HG, Chen Q, Wolfram JA, Richardson SL, Liner A, Siedlak SL, Zhu X, Ziats NP, Fujioka H, Felsher DW, Castellani RJ, Valencik ML, McDonald JA, Hoit BD, Lesnefsky EJ, Smith MA - PLoS ONE (2009)

The expression of Myc leads to a decreased rate of dinitrophenol uncoupled respiration when glutamate+malate and succinate+rotenone were used as complex I and complex II substrates compared to the mitochondria from Myc-OFF or single transgenic mice (Single Tg) (Panel A).Myc did not affect the oxidation of TMPD-ascorbate (Panel A). Direct measurement of electron transport chain enzyme activity shows that Myc decreased activities of complex I, NCR (NADH cytochrome c oxidoreductase), and complex III (Panel B). Data are expressed as mean±SEM; * p<0.05 vs. Myc-OFF and Single Tg. n = 5 for Myc-ON and Myc-OFF, and n = 4 for Single Tg.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2747003&req=5

pone-0007172-g008: The expression of Myc leads to a decreased rate of dinitrophenol uncoupled respiration when glutamate+malate and succinate+rotenone were used as complex I and complex II substrates compared to the mitochondria from Myc-OFF or single transgenic mice (Single Tg) (Panel A).Myc did not affect the oxidation of TMPD-ascorbate (Panel A). Direct measurement of electron transport chain enzyme activity shows that Myc decreased activities of complex I, NCR (NADH cytochrome c oxidoreductase), and complex III (Panel B). Data are expressed as mean±SEM; * p<0.05 vs. Myc-OFF and Single Tg. n = 5 for Myc-ON and Myc-OFF, and n = 4 for Single Tg.
Mentions: Based on our ultrastructural findings, and since defects in mitochondrial metabolism contribute to the pathogenesis and progression of heart failure, we explored whether functional deficits in mitochondrial metabolism were associated with the observed changes in size and number of mitochondria in Myc-ON mice. Myc-ON expression led to a decrease in protein yield of mitochondria compared to the Myc-OFF or single transgenic mice (Table 2). Moreover, the specific activity of citrate synthase, a mitochondrial marker enzyme, was decreased in the mitochondria from Myc-ON mice compared to the mitochondria from Myc-OFF or single transgenic mice (Myc-ON 3540±160* mU/mg protein, n = 5 , p<0.05 vs. both Myc-OFF 4159±144, n = 5, and Single Tg 4105±156, n = 4). With glutamate plus malate as the donor of reducing equivalents to complex I, the rate of state 3 respiration was lower in Myc-ON compared to the Myc-OFF or single transgenic mice and state 4 respiration was also decreased in Myc-ON mitochondria compared to other groups. In contrast, the respiratory control ratio (RCR, state3/state4) was higher in Myc-ON mouse mitochondria compared to the Myc-OFF or single groups and there was no difference in the ADP/O ratio among groups (Table 2). With succinate plus rotenone as the complex II substrate, respiration was also decreased in Myc-ON mitochondria. The decreased oxidation in the presence of dinitrophenol localizes the defect to the mitochondrial electron transport chain (Table 2, Figure 8).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States of America. hyoung-gon.lee@case.edu

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.

Show MeSH
Related in: MedlinePlus