Mechanical and Energetic Consequences of HCM-Causing Mutations

Journal of Cardiovascular Translational Research - Tập 2 - Trang 441-451 - 2009
Cecilia Ferrantini1, Alexandra Belus1, Nicoletta Piroddi1, Beatrice Scellini1, Chiara Tesi1, Corrado Poggesi1,2
1Department of Physiology and Center of Molecular Medicine (C.I.M.M.B.A.), University of Florence, Florence, Italy
2Department of Physiology, University of Florence, Florence, Italy

Tóm tắt

Hypertrophic cardiomyopathy (HCM) was the first inherited heart disease to be characterized at the molecular genetic level with the demonstration that it is caused by mutations in genes that encode different components of the cardiac sarcomere. Early functional in vitro studies have concluded that HCM mutations cause a loss of sarcomere mechanical function. Hypertrophy would then follow as a compensatory mechanism to raise the work and power output of the affected heart. More recent in vitro and mouse model studies have suggested that HCM mutations enhance contractile function and myofilament Ca2+ sensitivity and impair cardiac myocyte energetics. It has been hypothesized that these changes may result in cardiac myocyte energy depletion due to inefficient ATP utilization and also in altered myoplasmic Ca2+ handling. The problems encountered in reaching a definitive answer on the effects of HCM mutations are discussed. Though direct analysis of the altered functional characteristics of HCM human cardiac sarcomeres has so far lagged behind the in vitro and mouse studies, recent work with mechanically isolated skinned myocytes and myofibrils from affected human hearts seem to support the energy depletion hypothesis. If further validated in the human heart, this hypothesis would identify tractable therapeutic targets that suggest that HCM, perhaps more than any other cardiomyopathy, will be amenable to disease-modifying therapy.

Tài liệu tham khảo

Arad, M., Benson, D. W., Perez-Atayde, A. R., McKenna, W. J., Sparks, E. A., Kanter, R. J., et al. (2002). Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy. J Clin Invest, 109, 357–362. Ashrafian, H., Redwood, C., Blair, E., & Watkins, H. (2003). Hypertrophic cardiomyopathy: a paradigm for myocardial energy depletion. Trends in Genetics, 19, 263–268. Ashrafian, H., & Watkins, H. (2007). Reviews of translational medicine and genomics in cardiovascular disease: new disease taxonomy and therapeutic implications. J Am Coll Cardiol, 49, 1251–1264. Baudenbacher, F., Schober, T., Pinto, J. R., Sidorov, V. Y., Hilliard, F., Solaro, R. J., et al. (2008). Myofilament Ca2+ sensitization causes susceptibility to cardiac arrhythmia in mice. J Clin Invest, 118, 3893–3903. Bing, W., Knott, A., Redwood, C., Esposito, G., Purcell, I., Watkins, H., et al. (2000). Effect of hypertrophic cardiomyopathy mutations in human cardiac muscle alpha-tropomyosin (Asp175Asn and Glu180Gly) on the regulatory properties of human cardiac troponin determined by in vitro motility assay. J Mol Cel Cardiol, 32, 1489–1498. Blair, E., Redwood, C., Ashrafian, H., Oliveira, M., Broxholme, J., Kerr, B., et al. (2001). Mutations in the gamma(2) subunit of AMP-activated protein kinase cause familial hypertrophic cardiomyopathy: evidence for the central role of energy compromise in disease pathogenesis. Human molecular genetics, 10, 1215–1220. Belus, A., Piroddi, N., Scellini, B., Tesi, C., D’Amati, G., Girolami, F., et al. (2008). The FHC-associated myosin mutation R403Q accelerates tension generation and relaxation of human cardiac myofibrils. J Physiol, 586, 3639–3644. Bonne, G., Carrier, L., Bercovici, J., Cruaud, C., Richard, P., Hainque, B., et al. (1995). Cardiac myosin binding protein-C gene splice acceptor site mutation is associated with familial hypertrophic cardiomyopathy. Nat Genet, 11, 438–440. Borbély, A., van der Velden, J., Bronzwaer, J. G. F., Papp, Z., Édes, I., Stienen, G. J. M., et al. (2005). Cardiomyocyte stiffness in diastolic heart failure. Circulation, 111, 774–781. Bottinelli, R., Coviello, D. A., Redwood, C. S., Pellegrino, M. A., Maron, B. J., Spirito, P., et al. (1998). A mutant tropomyosin that causes hypertrophic cardiomyopathy is expressed in vivo and associated with an increased calcium sensitivity. Circ Res, 82, 106–115. Crilley, J. G., Boehm, E. A., Blair, E., Rajagopalan, B., Blamire, A. M., Styles, P., et al. (2003). Hypertrophic cardiomyopathy due to sarcomeric gene mutations is characterized by impaired energy metabolism irrespective of the degree of hypertrophy. J Am Coll Cardiol, 41, 1776–1782. Cuda, G., Fananapazir, L., Zhu, W. S., Sellers, J. R., & Epstein, N. D. (1993). Skeletal muscle expression and abnormal function of beta-myosin in hypertrophic cardiomyopathy. J Clin Invest, 91, 2861–2865. Dyer, E., Jacques, A., Burch, M., Kaski, J. P., & Marston, S. (2008). Functional effects of DCM mutation G159D in troponin C from an explanted heart. J Mol Cell Cardiol, 44, 729–730. Elliott, K., Watkins, H., & Redwood, C. S. (2000). Altered regulatory properties of human cardiac troponin I mutants that cause hypertrophic cardiomyopathy. J Biol Chem, 275, 22069–22074. Fujita, H., Sugiura, S., Momomura, S., Omata, M., Sugi, H., & Sutoh, K. (1997). Characterization of mutant myosins of Dictyostelium discoideum equivalent to human familial hypertrophic cardiomyopathy mutants. Molecular force level of mutant myosins may have a prognostic implication. J Clin Invest, 99, 1010–1015. Geisterfer-Lowrance, A. A., Christe, M., Conner, D. A., Ingwall, J. S., Schoen, F. J., Seidman, C. E., et al. (1996). A mouse model of familial hypertrophic cardiomyopathy. Science, 272, 731–734. Geisterfer-Lowrance, A. A., Kass, S., Tanigawa, G., Vosberg, H. P., McKenna, W., Seidman, C. E., et al. (1990). A molecular basis for familial hypertrophic cardiomyopathy: a beta cardiac myosin heavy chain gene missense mutation. Cell, 62, 999–1006. Hajjar, R. J., Gwathmey, J. K., Briggs, G. M., & Morgan, J. P. (1988). Differential effect of DPI 201–106 on the sensitivity of the myofilaments to Ca2+ in intact and skinned trabeculae from control and myopathic human hearts. J Clin Invest, 82, 1578–1584. He, H., Javadpour, M. M., Latif, F., Tardiff, J. C., & Ingwall, J. S. (2007). R-92L and R-92W mutations in cardiac troponin T lead to distinct energetic phenotypes in intact mouse hearts. Biophys J, 93, 1834–1844. Ho, C., Sweitzer, N. K., McDonough, B., Maron, B. J., Casey, S. A., Seidman, J. G., et al. (2002). Assessment of diastolic function with doppler tissue imaging to predict genotype in preclinical hypertrophic cardiomyopathy. Circulation, 105, 2992–2997. Hoffmann, B., Schmidt-Traub, H., Perrot, A., Osterziel, K. J., & Gessner, R. (2001). First mutation in cardiac troponin C, L29Q, in a patient with hypertrophic cardiomyopathy. Hum Mutat, 17, 524. Hofmann, P. A., Hartzell, H. C., & Moss, R. L. (1991). Alterations in Ca2+ sensitive tension due to partial extraction of C-protein from rat skinned cardiac myocytes and rabbit skeletal muscle fibers. J Gen Physiol, 97, 1141–1163. Homsher, E., Lee, D. M., Morris, C., Pavlov, D., & Tobacman, L. S. (2000). Regulation of force and unloaded sliding speed in single thin filaments: effects of regulatory proteins and calcium. J Physiol, 524, 233–243. Jarcho, J. A., McKenna, W., Pare, J. A., Solomon, S. D., Holcombe, R. F., Dickie, S., et al. (1989). Mapping a gene for familial hypertrophic cardiomyopathy to chromosome 14q1. N Engl J Med, 321, 1372–1378. Jacques, A., Hoskins, A., Kentish, J. C., & Marston, S. B. (2008). From genotype to phenotype: a longitudinal study of a patient with hypertrophic cardiomyopathy due to a mutation in the MYBPC3 gene. J Muscle Res Cell Motility, 29, 239–246. Javadpour, M. M., Tardiff, J. C., Pinz, I., & Ingwall, J. S. (2003). Decreased energetics in murine hearts bearing the R92Q mutation in cardiac troponin T. J Clin Invest, 112, 768–775. Keller, D. I., Coirault, C., Rau, T., Cheav, T., Weyand, M., Amann, K., et al. (2004). Human homozygous R403W mutant cardiac myosin presents disproportionate enhancement of mechanical and enzymatic properties. J Mol Cell Cardiol, 36, 355–362. Kimura, A., Harada, H., Park, J. E., Nishi, H., Satoh, M., Takahashi, M., et al. (1997). Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy. Nat Genet, 16, 379–382. Knollmann, B. C., Blatt, S. A., Horton, K., de Freitas, F., Miller, T., Bell, M., et al. (2001). Inotropic stimulation induces cardiac dysfunction in transgenic mice expressing a troponin T (I79N) mutation linked to familial hypertrophic cardiomyopathy. J Biol Chem, 276, 10039–10048. Kulikovskaya, I., McClellan, G., Levine, R., & Winegrad, S. (2003). Effect of extraction of myosin binding protein C on contractility of rat heart. Am J Physiol Heart Circ Physiol, 285, H857–H865. Landstrom, A. P., Parvatiyar, M. S., Pinto, J. R., Marquardt, M. L., Bos, J. M., Tester, D. J., et al. (2008). Molecular and functional characterization of novel hypertrophic cardiomyopathy susceptibility mutations in TNNC1-encoded troponin C. J Mol Cell Cardiol, 45(2), 281–288. Lankford, E. B., Epstein, N. D., Fananapazir, L., & Sweeney, H. L. (1995). Abnormal contractile properties of muscle fibers expressing beta-myosin heavy chain gene mutations in patients with hypertrophic cardiomyopathy. J Clin Invest, 95, 1409–1414. Lin, D., Bobkova, A., Homsher, E., & Tobacman, L. S. (1996). Altered cardiac troponin T in vitro function in the presence of a mutation implicated in familial hypertrophic cardiomyopathy. J Clin Invest, 97(12), 2842–8. Lowey, S. (2002). Functional consequences of mutations in the myosin heavy chain at sites implicated in familial hypertrophic cardiomyopathy. Trends Cardiovasc Med, 12, 348–354. Lowey, S., Lesko, M., Rovner, A. S., Hodges, A. R., White, S. L., Low, R. B., et al. (2008). Functional effects of the hypertrophic cardiomyopathy R403Q mutation are different in an alpha- or beta-myosin heavy chain backbone. J Biol Chem, 283, 20579–2089. Marian, A. J. (2000). Pathogenesis of diverse clinical and pathological phenotypes in hypertrophic cardiomyopathy. Lancet, 355, 58–60. Marian, A. J., & Roberts, R. (2001). The molecular genetic basis for hypertrophic cardiomyopathy. J Mol Cell Cardiol, 33(4), 655–670. Miller, G., Maycock, J., White, E., Peckham, M., & Calaghan, S. (2003). Heterologous expression of wild-type and mutant beta-cardiac myosin changes the contractile kinetics of cultured mouse myotubes. J Physiol, 548, 167–174. Mogensen, J., Klausen, I. C., Pedersen, A. K., Egeblad, H., Bross, P., Kruse, T. A., et al. (1999). Alpha-cardiac actin is a novel disease gene in familial hypertrophic cardiomyopathy. J Clin Invest, 103, R39–43. Morano, I., Bletz, C., Wojciechowski, R., & Ruegg, J. C. (1991). Modulation of crossbridge kinetics by myosin isoenzymes in skinned human heart fibers. Circ Res, 68, 614–618. Morimoto, S., Yanaga, F., Minatami, R., & Ohtsuki, I. (1998). Ca2+-sensitizing effects of the mutations at Ile-79 and Arg-92 of troponin T in hypertrophic cardiomyopathy. Am J Physiol, 275, C200–C207. Mulieri, L. A., Barnes, W., Leavitt, B. J., Ittleman, F. P., LeWinter, M. M., Alpert, N. R., et al. (2002). Alterations of myocardial dynamic stiffness implicating abnormal crossbridge function in human mitral regurgitation heart failure. Circ Res, 90, 66–72. Narolska, N. A., van Loon, R. B., Boontje, N. M., Zaremba, R., Penas, S. E., Russell, J., et al. (2005). Myocardial contraction is 5-fold more economical in ventricular than in atrial human tissue. Cardiovasc Res, 65, 221–229. Palmiter, K. A., Tyska, M. J., Haeberle, J. R., Alpert, N. R., Fananapazir, L., & Warshaw, D. M. (2000). R403Q and L908V mutant beta-cardiac myosin from patients with familial hypertrophic cardiomyopathy exhibit enhanced mechanical performance at the single molecule level. J Muscle Res Cell Motil, 21, 609–620. Pinto, J. R., Parvatiyar, M. S., Jones, M. A., Liang, J., Ackerman, M. J., & Potter, J. D. (2009). A functional and structural study of troponin C mutations related to hypertrophic cardiomyopathy. J Biol Chem, 284, 19090–19100. Piroddi, N., Belus, A., Scellini, B., Tesi, C., Giunti, G., Cerbai, E., et al. (2007). Tension generation and relaxation in single myofibrils from human atrial and ventricular myocardium. Pflugers Arch, 454, 63–73. Poggesi, C., Tesi, C., & Stehle, R. (2005). Sarcomeric determinants of striated muscle relaxation kinetics. Pflügers Arch, 449, 505–517. Poetter, K., Jiang, H., Hassanzadeh, S., Master, S. R., Chang, A., Dalakas, M. C., et al. (1996). Mutations in either the essential or regulatory light chains of myosin are associated with a rare myopathy in human heart and skeletal muscle. Nat Genet, 13, 63–69. Redwood, C., Lohmann, K., Bing, W., Esposito, G. M., Elliott, K., Abdulrazzak, H., et al. (2000). Investigation of a truncated cardiac troponin T that causes familial hypertrophic cardiomyopathy: Ca2+ regulatory properties of reconstituted thin filaments depend on the ratio of mutant to wild-type protein. Circ Res, 86, 1146–1152. Richard, P., Charron, P., Carrier, L., Ledeuil, C., Cheav, T., Pichereau, C., et al. (2003). Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation, 107, 2227–2232. Robinson, P., Griffiths, P. J., Watkins, H., & Redwood, C. S. (2007). Dilated and hypertrophic cardiomyopathy mutations in troponin and alpha-tropomyosin have opposing effects on the calcium affinity of cardiac thin filaments. Circ Res, 101, 1266–1273. Robinson, P., Mirza, M., Knott, A., Abdulrazzak, H., Willott, R., Marston, S., et al. (2002). Alterations in thin filament regulation induced by a human cardiac troponin T mutant that causes dilated cardiomyopathy are distinct from those induced by troponin T mutants that cause hypertrophic cardiomyopathy. J Biol Chem, 277, 40710–40716. Roopnarine, O., & Leinwand, L. A. (1998). Functional analysis of myosin mutations that cause familial hypertrophic cardiomyopathy. Biophys J, 75, 3023–3030. Sachs, F. (1999). Practical limits on the maximal speed of solution exchange for patch clamp experiments. Biophys J, 1999(77), 682–690. Sata, M., & Ikebe, M. (1996). Functional analysis of the mutations in the human cardiac beta-myosin that are responsible for familial hypertrophic cardiomyopathy. Implication for the clinical outcome. J Clin Invest, 98, 2866–2873. Satoh, M., Takahashi, M., Sakamoto, T., Hiroe, M., Marumo, F., & Kimura, A. (1999). Structural analysis of the titin gene in hypertrophic cardiomyopathy: identification of a novel disease gene. Biochem Biophys Res Commun, 262, 411–417. Seidman, J. G., & Seidman, C. (2001). The genetic basis for cardiomyopathy: from mutation identification to mechanistic paradigms. Cell, 104, 557–567. Spindler, M., Saupe, K. W., Christe, M. E., Sweeney, H. L., Seidman, C. E., Seidman, J. G., et al. (1998). Diastolic dysfunction and altered energetics in the alphaMHC403/+ mouse model of familial hypertrophic cardiomyopathy. J Clin Invest, 101, 1775–1783. Stehle, R., Solzin, J., Iorga, B., & Poggesi, C. (2009). Insights into the kinetics of Ca2+-regulated contraction and relaxation from myofibril studies. Pflügers Arch, 458, 337–357. Sweeney, H. L., Feng, H. S., Yang, Z., & Watkins, H. (1998). Functional analyses of troponin T mutations that cause hypertrophic cardiomyopathy: insights into disease pathogenesis and troponin function. Proc Natl Acad Sci USA, 95, 14406–14410. Sweeney, H. L., Straceski, A. J., Leinwand, L. A., Tikunov, B. A., & Faust, L. (1994). Heterologous expression of a cardiomyopathic myosin that is defective in its actin interaction. J Biol Chem, 269, 1603–1605. Tardiff, J. C., Hewett, T. E., Palmer, B. M., Olsson, C., Factor, S. M., Moore, R. L., et al. (1999). Cardiac troponin T mutations result in allele-specific phenotypes in a mouse model for hypertrophic cardiomyopathy. J Clin Invest, 104, 469–481. Tesi, C., Colomo, F., Nencini, S., Piroddi, N., & Poggesi, C. (2000). The effect of inorganic phosphate on force generation in single myofibrils from rabbit skeletal muscle. Biophys J, 78, 3081–3092. Tesi, C., Piroddi, N., Colomo, F., & Poggesi, C. (2002). Relaxation kinetics following sudden Ca2+ reduction in single myofibrils from skeletal muscle. Biophys J, 83, 2142–2151. Thierfelder, L., Watkins, H., MacRae, C., Lamas, R., McKenna, W., Vosberg, H. P., et al. (1994). Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere. Cell, 77, 701–712. Tyska, M. J., Hayes, E., Giewat, M., Seidman, C. E., Seidman, J. G., & Warshaw, D. M. (2000). Single molecule mechanics of R403Q cardiac myosin isolated from the mouse model of familial hypertrophic cardiomyopathy. CircRes, 86, 737–744. van der Velden, J., Klein, L. J., Zaremba, R., Boontje, N. M., Huybregts, M. A., Stooker, W., et al. (2001). Effects of calcium, inorganic phosphate, and pH on isometric force in single skinned cardiomyocytes from donor and failing human hearts. Circulation, 104, 1140–1146. van Dijk, S. J., Dooijes, D., dos Remedios, C., Michels, M., Lamers, J. M., Winegrad, S., et al. (2009). Cardiac myosin-binding protein C mutations and hypertrophic cardiomyopathy: haploin sufficiency, deranged phosphorylation, and cardiomyocyte dysfunction. Circulation, 119(11), 1473–1483. Vignier, N., Schlossarek, S., Fraysse, B., Mearini, G., Krämer, E., Pointu, H., et al. (2009). Nonsense-mediated mRNA decay and ubiquitin-proteasome system regulate cardiac myosin-binding protein C mutant levels in cardiomyopathic mice. Circ Res, 105, 239–248. Watkins, H., Conner, D., Thierfelder, L., Jarcho, J. A., MacRae, C., McKenna, W. J., et al. (1995). Mutations in the cardiac myosin binding protein-C gene on chromosome 11 cause familial hypertrophic cardiomyopathy. Nat Genet, 11, 434–437. Wolff, M. R., Buck, S. H., Stoker, S. W., Greaser, M. L., & Mentzer, R. M. (1996). Myofibrillar calcium sensitivity of isometric tension is increased in human dilated cardiomyopathies: role of altered beta-adrenergically mediated protein phosphorylation. J Clin Invest, 98, 167–176. Yamashita, H., Tyska, M. J., Warshaw, D. M., Lowey, S., & Trybus, K. M. (2000). Functional consequences of mutations in the smooth muscle myosin heavy chain at sites implicated in familial hypertrophic cardiomyopathy. J Biol Chem, 275, 28045–28052.