Cell Metabolism

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Heart-Healthy Hypertrophy
Chinmay M. Trivedi1,2,3 and Jonathan A. Epstein1,2,3,*
of Cell and Developmental Biology Institute 3Institute for Regenerative Medicine University of Pennsylvania, Philadelphia, PA 19104, USA *Correspondence: epsteinj@mail.med.upenn.edu DOI 10.1016/j.cmet.2010.12.012
2Cardiovascular 1Department

m et al., 2010) Exercise induces growth of heart muscle cells and heart size. A new report in Cell (Bostro suggests that mice also respond to exercise with increased cardiac myocyte proliferation, and the molecular regulators of this pathway are linked to maladaptive and pathologic responses to cardiac stresses such as pressure overload.
Shortly after birth, cardiomyocyte proliferation largely ceases, and continued growth of the heart is achieved by further increases in the size of pre-existing cardiomyocytes (hypertrophy). Conditions that place a physiologic gradual increase in demand on the heart, such as endurance training or pregnancy, can enhance cardiac growth rates and pump function (physiologic hypertrophy). On the other hand, pathologic stress such as sustained pressure overload resulting from high blood pressure or valvular abnormalities, can lead to a maladaptive form of cardiac growth (pathologic hypertrophy), which is associated with loss of cardiomyocytes, brosis, progressive cardiac dysfunction, and heart failure. At the molecular level, the similarities and distinctions between physiologic and pathologic hypertrophy have remained largely mysterious. m and colleagues reRecently, Bostro ported a novel and provocative molecular relationship between these cellular pathways involving CCAAT/enhancer-binding protein (C/EBP) b, suggesting that one mechanism by which endurance exercise enhances cardiac function is by inducing m cardiomyocyte proliferation (Bostro et al., 2010). To compare transcriptional programs regulating pathologic and physiologic m et al. utilized hypertrophy in mice, Bostro a quantitative PCR-based screening method, termed Quanttrx (Gupta et al., 2010), and cardiac samples from young adult mice (12 weeks of age) after thoracic aortic constriction (TAC) surgery, a model of pathologic hypertrophy, or swimming exercise, a model of physiologic hypertrophy. They observed little overlap between the transcriptional programs activated by these different forms of stimulation. After further validation, the authors chose to focus on C/EBPb, which was dramatically reduced in exercised hearts (by about 60%), but not in those exposed to pressure overload. C/EBPb is a basic-helix-loop-helix transcription factor expressed in a variety of tissues including fat, liver, and heart. Since C/EBPb levels were reduced with exercise, m et al. examined heterozygous Bostro mice with partial loss of C/EBPb function. These animals exhibited signs of endurance training even without exercise. Partial loss of C/EBPb was associated with an increase in Cbp/p300-interacting transactivator with ED-rich carboxy-terminal domain (CITED) 4 expression, and this increase was necessary for the manifestation of reduced C/EPb activity. This suggests that reduced C/EBPb function and resulting increases in CITED4 are at least partially responsible for the molecular consequences of endurance training on the heart. Heterozygous C/EBPb mice not only mimic aspects of exercise-trained animals, but are also resistant to the maladaptive responses normally seen after exposure to pressure overload. Heterozygous animals show a less steep decline in cardiac function and fewer signs of heart failure than wild-type animals after TAC. Although not examined in this study, it will be interesting to determine if endurance training provides the same protection to pathologic stress and if the degree of protection is enhanced by C/EBPb haploinsufciency. Furthermore, it will be important to conrm that the effects of C/EBPb haploinsufciency are due to loss of function within cardiomyocytes by analyzing inducible tissue-specic deletion in adult heart cells. How is C/EBPb-regulated in response to exercise, and how does its loss result in protection from pathologic stress? The insulin-like growth factor (IGF) pathway has been implicated in physiologic hypertrophy and control of cell size via activation of thymoma viral protooncogene (AKT) and downstream signaling components (DeBosch et al., m 2006; Dorn and Force, 2005). Bostro et al. showed that AKT activation results in downregulation of C/EBP (Figure 1). Furthermore, C/EBPb can inhibit binding of serum response factor (SRF) to DNA, providing a potential mechanism for regulation of downstream signaling during hypertrophy. SRF activity in the heart is potently regulated by the myocardin family of transcriptional coactivators and by the homeodomain-containing protein Hopx. These transcriptional complexes are implicated in pathologic hypertrophy downstream of neurohormonal and calcium-mediated signals (Kook et al., 2003; Wang et al., 2001). SRF functionally interacts with other cardiac-specic transcription factors including Nkx2-5 and Gata4. Loss of C/EBPb as a result of endurance training might result in enhanced SRF transcriptional activity and activation of pathways associated with pathologic hypertrophy; yet, pathologic hypertrophy is reduced in C/EBPb heterozygotes. Clearly, a more detailed understanding of the relationship of C/EBPb to other hypertrophic signaling cascades is required. In this regard, it is worth noting that C/EBPb can interact with nuclear factor of activated T cells (NFAT) and modulate its activity

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Cell Metabolism

(Oh et al., 2010), and NFAT If exercise truly enhances can modulate pathologic the hearts ability to prolifhypertrophy downstream of erate and regenerate, calcium signaling. perhaps recovery after m et al. also noted Bostro myocardial injury would be a marked increase in DNA enhanced after endurance synthesis within cardiomyotraining or in C/EBPb heterocytes of endurance-trained zygous mice. If so, C/EBPb animals. They suggest that may be the tip of a targetable cardiac myocyte proliferation pathway for cardiac protecis enhanced by exercise, and tion and regeneration in huthat myocyte hyperplasia mans, and future studies (more cells) may account for may provide us with yet some of the benecial effects more incentive to exercise. of exercise, in addition to REFERENCES effects mediated by myocyte hypertrophy. Bergmann, O., Bhardwaj, R.D., The ability of adult cardiac Bernard, S., Zdunek, S., Barnabemyoctyes to proliferate Heider, F., Walsh, S., Zupicich, J., Alkass, K., Buchholz, B.A., Druid, remains controversial. H., et al. (2009). Science 324, Classic teaching suggests 98102. myocyte proliferation ceases Bersell, K., Arab, S., Haring, B., and shortly after birth, but recent Kuhn, B. (2009). Cell 138, 257270. reports indicate that this may not be the case (Bersell m, P., Mann, N., Wu, J., QuinBostro kova , tero, P.A., Plovie, E.R., Pana et al., 2009), and some turnD., Gupta, R.K., Xiao, C., MacRae, over of adult myocytes may C.A., Rosenzweig, A., and Spiegeloccur in both mice and human, B.M. (2010). Cell 143, 1072 Figure 1. Signaling Pathways Regulating Physiologic and 1083. mans (Bergmann et al., 2009; Pathologic Cardiac Hypertrophy Hsieh et al., 2007). Studies of 2+ Neurohormonal and calcium (Ca ) -mediated pathways can activate signaling DeBosch, B., Treskov, I., Lupu, T.S., cardiomyocyte proliferation Weinheimer, C., Kovacs, A., Courcascades in cardiac myocytes that lead to activation of maladaptive hypertois, M., and Muslin, A.J. (2006). trophy. Exercise, pregnancy, and other physiologic growth stimuli can act are complicated by the fact Circulation 113, 20972104. through insulin-like growth factor (IGF) 1 to stimulate phosphoinositide-3 that these cells can be polykinase (PI3K) and Akt, which inhibits C/EBPb. C/EBPb may function through ploid and undergo DNA Dorn, G.W., 2nd, and Force, T. inhibition of CITED4 to regulate physiologic hypertrophy and myocyte prolifer(2005). J. Clin. Invest. 115, 527537. synthesis and nuclear division ation, and it may also affect the activity of serum response factor (SRF) to modulate pathologic responses (dotted lines). to produce multinucleated Gupta, R.K., Arany, Z., Seale, P., cells without undergoing Mepani, R.J., Ye, L., Conroe, H.M., cellular division. DNA synthesis and incorporated BrdU). Hence, it remains Roby, Y.A., Kulaga, H., Reed, R.R., and Spiegelpolyploidy are increased under conditions unclear how many myocytes actually man, B.M. (2010). Nature 464, 619623. of cardiac stress and hypertrophy, a undergo cell division in response to exer- Hsieh, P.C., Segers, V.F., Davis, M.E., MacGillivresponse requiring cyclinG1 (Liu et al., cise, how many new myocytes are ray, C., Gannon, J., Molkentin, J.D., Robbins, J., 2010). Thus, the demonstration of DNA produced, and to what degree this and Lee, R.T. (2007). Nat. Med. 13, 970974. synthesis does not necessarily mean that accounts for benecial effects. It will be Kook, H., Lepore, J.J., Gitler, A.D., Lu, M.M., Wingmore myocytes have been produced. of interest to apply alternative quantitative Man Yung, W., Mackay, J., Zhou, R., Ferrari, V., m et al. addressed this issue by approaches, such as those used to esti- Gruber, P., and Epstein, J.A. (2003). J. Clin. Invest. Bostro 112, 863871. examining expression of aurora B kinase, mate myocyte turnover after myocardial which is a necessary component of the infarction or pressure overload (Hsieh Liu, Z., Yue, S., Chen, X., Kubin, T., and Braun, T. contractile ring mediating cytoplasmic et al., 2007), to validate these ndings. It (2010). Circ. Res. 106, 14981506. separation and cell division. The paper is also important to determine if similar Oh, M., Dey, A., Gerard, R.D., Hill, J.A., and identies an increase in aurora B kinase changes in myocyte proliferation occur in Rothermel, B.A. (2010). J. Biol. Chem. 285, expressing myocytes after exercise, older animals, since the mice used in this 1662316631. although the numbers appear small study were relatively young (12 weeks Wang, D., Chang, P.S., Wang, Z., Sutherland, L., (0.2% of myocytes after exercise old) and proliferation potential likely Richardson, J.A., Small, E., Krieg, P.A., and Olson, E.N. (2001). Cell 105, 851862. compared to >6% of myocytes that had decreases with age.

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