Omecamtiv mecarbil lowers the contractile deficit in a mouse model of nebulin-based nemaline myopathy


Autoři: Johan Lindqvist aff001;  Eun-Jeong Lee aff001;  Esmat Karimi aff001;  Justin Kolb aff001;  Henk Granzier aff001
Působiště autorů: Department of Cellular and Molecular Medicine, University of Arizona, Tucson, Arizona, United States of America aff001
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: 10.1371/journal.pone.0224467

Souhrn

Nemaline myopathy (NEM) is a congenital neuromuscular disorder primarily caused by nebulin gene (NEB) mutations. NEM is characterized by muscle weakness for which currently no treatments exist. In NEM patients a predominance of type I fibers has been found. Thus, therapeutic options targeting type I fibers could be highly beneficial for NEM patients. Because type I muscle fibers express the same myosin isoform as cardiac muscle (Myh7), the effect of omecamtiv mecarbil (OM), a small molecule activator of Myh7, was studied in a nebulin-based NEM mouse model (Neb cKO). Skinned single fibers were activated by exogenous calcium and force was measured at a wide range of calcium concentrations. Maximal specific force of type I fibers was much less in fibers from Neb cKO animals and calcium sensitivity of permeabilized single fibers was reduced (pCa50 6.12 ±0.08 (cKO) vs 6.36 ±0.08 (CON)). OM increased the calcium sensitivity of type I single muscle fibers. The greatest effect occurred in type I fibers from Neb cKO muscle where OM restored the calcium sensitivity to that of the control type I fibers. Forces at submaximal activation levels (pCa 6.0–6.5) were significantly increased in Neb cKO fibers (~50%) but remained below that of control fibers. OM also increased isometric force and power during isotonic shortening of intact whole soleus muscle of Neb cKO mice, with the largest effects at physiological stimulation frequencies. We conclude that OM has the potential to improve the quality of life of NEM patients by increasing the force of type I fibers at submaximal activation levels.

Klíčová slova:

Cardiac muscles – Fast-twitch muscle fibers – Mouse models – Muscle fibers – Myosins – Skeletal muscles – Slow-twitch muscle fibers – Soleus muscles


Zdroje

1. Wang K. Purification of titin and nebulin. Methods Enzymol. 1982;85 Pt B:264–74. doi: 10.1016/0076-6879(82)85025-8 6896900.

2. Labeit S, Kolmerer B. The complete primary structure of human nebulin and its correlation to muscle structure. J Mol Biol. 1995;248(2):308–15. doi: 10.1016/s0022-2836(95)80052-2 7739042.

3. Chandra M, Mamidi R, Ford S, Hidalgo C, Witt C, Ottenheijm C, et al. Nebulin alters cross-bridge cycling kinetics and increases thin filament activation: a novel mechanism for increasing tension and reducing tension cost. J Biol Chem. 2009;284(45):30889–96. doi: 10.1074/jbc.M109.049718 19736309

4. Ottenheijm CA, Granzier H. Lifting the nebula: novel insights into skeletal muscle contractility. Physiology (Bethesda). 2010;25(5):304–10. doi: 10.1152/physiol.00016.2010 20940435.

5. Bang ML, Caremani M, Brunello E, Littlefield R, Lieber RL, Chen J, et al. Nebulin plays a direct role in promoting strong actin-myosin interactions. FASEB J. 2009;23(12):4117–25. doi: 10.1096/fj.09-137729 19679637

6. Tonino P, Pappas CT, Hudson BD, Labeit S, Gregorio CC, Granzier H. Reduced myofibrillar connectivity and increased Z-disk width in nebulin-deficient skeletal muscle. J Cell Sci. 2010;123(Pt 3):384–91. doi: 10.1242/jcs.042234 20053633

7. Pappas CT, Krieg PA, Gregorio CC. Nebulin regulates actin filament lengths by a stabilization mechanism. J Cell Biol. 2010;189(5):859–70. doi: 10.1083/jcb.201001043 20498015

8. Sanoudou D, Beggs AH. Clinical and genetic heterogeneity in nemaline myopathy—a disease of skeletal muscle thin filaments. Trends Mol Med. 2001;7(8):362–8. doi: 10.1016/s1471-4914(01)02089-5 11516997.

9. Lawlor MW, Ottenheijm CA, Lehtokari VL, Cho K, Pelin K, Wallgren-Pettersson C, et al. Novel mutations in NEB cause abnormal nebulin expression and markedly impaired muscle force generation in severe nemaline myopathy. Skelet Muscle. 2011;1(1):23. doi: 10.1186/2044-5040-1-23 21798101

10. Lehtokari VL, Kiiski K, Sandaradura SA, Laporte J, Repo P, Frey JA, et al. Mutation update: the spectra of nebulin variants and associated myopathies. Hum Mutat. 2014;35(12):1418–26. doi: 10.1002/humu.22693 25205138

11. Wallgren-Pettersson C, Sewry CA, Nowak KJ, Laing NG. Nemaline myopathies. Semin Pediatr Neurol. 2011;18(4):230–8. doi: 10.1016/j.spen.2011.10.004 22172418.

12. Ottenheijm CA, Hooijman P, DeChene ET, Stienen GJ, Beggs AH, Granzier H. Altered myofilament function depresses force generation in patients with nebulin-based nemaline myopathy (NEM2). J Struct Biol. 2010;170(2):334–43. doi: 10.1016/j.jsb.2009.11.013 19944167

13. Malfatti E, Lehtokari VL, Bohm J, De Winter JM, Schaffer U, Estournet B, et al. Muscle histopathology in nebulin-related nemaline myopathy: ultrastrastructural findings correlated to disease severity and genotype. Acta Neuropathol Commun. 2014;2:44. doi: 10.1186/2051-5960-2-44 24725366

14. Ryan MM, Schnell C, Strickland CD, Shield LK, Morgan G, Iannaccone ST, et al. Nemaline myopathy: a clinical study of 143 cases. Ann Neurol. 2001;50(3):312–20. doi: 10.1002/ana.1080 11558787.

15. Pelin K, Hilpela P, Donner K, Sewry C, Akkari PA, Wilton SD, et al. Mutations in the nebulin gene associated with autosomal recessive nemaline myopathy. Proc Natl Acad Sci U S A. 1999;96(5):2305–10. doi: 10.1073/pnas.96.5.2305 10051637

16. Wallgren-Pettersson C, Pelin K, Nowak KJ, Muntoni F, Romero NB, Goebel HH, et al. Genotype-phenotype correlations in nemaline myopathy caused by mutations in the genes for nebulin and skeletal muscle alpha-actin. Neuromuscul Disord. 2004;14(8–9):461–70. doi: 10.1016/j.nmd.2004.03.006 15336686.

17. Wang CH, Dowling JJ, North K, Schroth MK, Sejersen T, Shapiro F, et al. Consensus statement on standard of care for congenital myopathies. J Child Neurol. 2012;27(3):363–82. doi: 10.1177/0883073812436605 22431881

18. Teerlink JR, Clarke CP, Saikali KG, Lee JH, Chen MM, Escandon RD, et al. Dose-dependent augmentation of cardiac systolic function with the selective cardiac myosin activator, omecamtiv mecarbil: a first-in-man study. Lancet. 2011;378(9792):667–75. doi: 10.1016/S0140-6736(11)61219-1 21856480.

19. Psotka MA, Teerlink JR. Direct Myosin Activation by Omecamtiv Mecarbil for Heart Failure with Reduced Ejection Fraction. Handb Exp Pharmacol. 2017;243:465–90. doi: 10.1007/164_2017_13 28315072.

20. Woody MS, Greenberg MJ, Barua B, Winkelmann DA, Goldman YE, Ostap EM. Positive cardiac inotrope omecamtiv mecarbil activates muscle despite suppressing the myosin working stroke. Nat Commun. 2018;9(1):3838. doi: 10.1038/s41467-018-06193-2 30242219

21. Schiaffino S, Reggiani C. Molecular diversity of myofibrillar proteins: gene regulation and functional significance. Physiol Rev. 1996;76(2):371–423. doi: 10.1152/physrev.1996.76.2.371 8618961.

22. Schiaffino S, Reggiani C. Fiber types in mammalian skeletal muscles. Physiol Rev. 2011;91(4):1447–531. doi: 10.1152/physrev.00031.2010 22013216.

23. Tirrell TF, Cook MS, Carr JA, Lin E, Ward SR, Lieber RL. Human skeletal muscle biochemical diversity. J Exp Biol. 2012;215(Pt 15):2551–9. doi: 10.1242/jeb.069385 22786631

24. Hitomi Y, Kizaki T, Watanabe S, Matsumura G, Fujioka Y, Haga S, et al. Seven skeletal muscles rich in slow muscle fibers may function to sustain neutral position in the rodent hindlimb. Comp Biochem Physiol B Biochem Mol Biol. 2005;140(1):45–50. doi: 10.1016/j.cbpc.2004.09.021 15621508.

25. Li F, Buck D, De Winter J, Kolb J, Meng H, Birch C, et al. Nebulin deficiency in adult muscle causes sarcomere defects and muscle-type-dependent changes in trophicity: novel insights in nemaline myopathy. Hum Mol Genet. 2015;24(18):5219–33. doi: 10.1093/hmg/ddv243 26123491

26. Joureau B, de Winter JM, Stam K, Granzier H, Ottenheijm CA. Muscle weakness in respiratory and peripheral skeletal muscles in a mouse model for nebulin-based nemaline myopathy. Neuromuscul Disord. 2017;27(1):83–9. doi: 10.1016/j.nmd.2016.10.004 27890461.

27. Mamidi R, Li J, Gresham KS, Verma S, Doh CY, Li A, et al. Dose-Dependent Effects of the Myosin Activator Omecamtiv Mecarbil on Cross-Bridge Behavior and Force Generation in Failing Human Myocardium. Circ Heart Fail. 2017;10(10). doi: 10.1161/CIRCHEARTFAILURE.117.004257 29030372

28. Swenson AM, Tang W, Blair CA, Fetrow CM, Unrath WC, Previs MJ, et al. Omecamtiv Mecarbil Enhances the Duty Ratio of Human beta-Cardiac Myosin Resulting in Increased Calcium Sensitivity and Slowed Force Development in Cardiac Muscle. J Biol Chem. 2017;292(9):3768–78. doi: 10.1074/jbc.M116.748780 28082673

29. Cleland JG, Teerlink JR, Senior R, Nifontov EM, Mc Murray JJ, Lang CC, et al. The effects of the cardiac myosin activator, omecamtiv mecarbil, on cardiac function in systolic heart failure: a double-blind, placebo-controlled, crossover, dose-ranging phase 2 trial. Lancet. 2011;378(9792):676–83. doi: 10.1016/S0140-6736(11)61126-4 21856481.

30. Teerlink JR, Felker GM, McMurray JJV, Ponikowski P, Metra M, Filippatos GS, et al. Acute Treatment With Omecamtiv Mecarbil to Increase Contractility in Acute Heart Failure: The ATOMIC-AHF Study. J Am Coll Cardiol. 2016;67(12):1444–55. doi: 10.1016/j.jacc.2016.01.031 27012405.

31. Fukuda N, Wu Y, Farman G, Irving TC, Granzier H. Titin-based modulation of active tension and interfilament lattice spacing in skinned rat cardiac muscle. Pflugers Arch. 2005;449(5):449–57. doi: 10.1007/s00424-004-1354-6 15688246.

32. Ogut O, Granzier H, Jin JP. Acidic and basic troponin T isoforms in mature fast-twitch skeletal muscle and effect on contractility. Am J Physiol. 1999;276(5):C1162–70. doi: 10.1152/ajpcell.1999.276.5.C1162 10329966.

33. Chung CS, Hutchinson KR, Methawasin M, Saripalli C, Smith JE 3rd, Hidalgo CG, et al. Shortening of the elastic tandem immunoglobulin segment of titin leads to diastolic dysfunction. Circulation. 2013;128(1):19–28. doi: 10.1161/CIRCULATIONAHA.112.001268 23709671

34. Brenner B. The cross-bridge cycle in muscle. Mechanical, biochemical, and structural studies on single skinned rabbit psoas fibers to characterize cross-bridge kinetics in muscle for correlation with the actomyosin-ATPase in solution. Basic Res Cardiol. 1986;81 Suppl 1:1–15. doi: 10.1007/978-3-662-11374-5_1 2947559.

35. Ottenheijm CA, Hidalgo C, Rost K, Gotthardt M, Granzier H. Altered contractility of skeletal muscle in mice deficient in titin’s M-band region. J Mol Biol. 2009;393(1):10–26. doi: 10.1016/j.jmb.2009.08.009 19683008

36. Burkholder TJ, Fingado B, Baron S, Lieber RL. Relationship between muscle fiber types and sizes and muscle architectural properties in the mouse hindlimb. J Morphol. 1994;221(2):177–90. doi: 10.1002/jmor.1052210207 7932768.

37. Claflin DR, Faulkner JA. Shortening velocity extrapolated to zero load and unloaded shortening velocity of whole rat skeletal muscle. J Physiol. 1985;359:357–63. doi: 10.1113/jphysiol.1985.sp015589 3999042

38. Wang L, Kawai M. A re-interpretation of the rate of tension redevelopment (k(TR)) in active muscle. J Muscle Res Cell Motil. 2013;34(5–6):407–15. doi: 10.1007/s10974-013-9366-5 24162314

39. Kaplinsky E, Mallarkey G. Cardiac myosin activators for heart failure therapy: focus on omecamtiv mecarbil. Drugs Context. 2018;7:212518. doi: 10.7573/dic.212518 29707029

40. Liu Y, White HD, Belknap B, Winkelmann DA, Forgacs E. Omecamtiv Mecarbil modulates the kinetic and motile properties of porcine beta-cardiac myosin. Biochemistry. 2015;54(10):1963–75. doi: 10.1021/bi5015166 25680381.

41. Gollapudi SK, Reda SM, Chandra M. Omecamtiv Mecarbil Abolishes Length-Mediated Increase in Guinea Pig Cardiac Myofiber Ca(2+) Sensitivity. Biophys J. 2017;113(4):880–8. doi: 10.1016/j.bpj.2017.07.002 28834724

42. Nagy L, Kovacs A, Bodi B, Pasztor ET, Fulop GA, Toth A, et al. The novel cardiac myosin activator omecamtiv mecarbil increases the calcium sensitivity of force production in isolated cardiomyocytes and skeletal muscle fibres of the rat. Br J Pharmacol. 2015. doi: 10.1111/bph.13235 26140433

43. Kampourakis T, Zhang X, Sun YB, Irving M. Omecamtiv mercabil and blebbistatin modulate cardiac contractility by perturbing the regulatory state of the myosin filament. J Physiol. 2018;596(1):31–46. doi: 10.1113/JP275050 29052230

44. Piazzesi G, Caremani M, Linari M, Reconditi M, Lombardi V. Thick Filament Mechano-Sensing in Skeletal and Cardiac Muscles: A Common Mechanism Able to Adapt the Energetic Cost of the Contraction to the Task. Front Physiol. 2018;9:736. doi: 10.3389/fphys.2018.00736 29962967

45. Fusi L, Brunello E, Yan Z, Irving M. Thick filament mechano-sensing is a calcium-independent regulatory mechanism in skeletal muscle. Nat Commun. 2016;7:13281. doi: 10.1038/ncomms13281 27796302

46. Woodhead JL, Zhao FQ, Craig R, Egelman EH, Alamo L, Padron R. Atomic model of a myosin filament in the relaxed state. Nature. 2005;436(7054):1195–9. doi: 10.1038/nature03920 16121187.

47. Utter MS, Ryba DM, Li BH, Wolska BM, Solaro RJ. Omecamtiv Mecarbil, a Cardiac Myosin Activator, Increases Ca2+ Sensitivity in Myofilaments With a Dilated Cardiomyopathy Mutant Tropomyosin E54K. J Cardiovasc Pharmacol. 2015;66(4):347–53. doi: 10.1097/FJC.0000000000000286 26065842

48. Kolb J, Li F, Methawasin M, Adler M, Escobar YN, Nedrud J, et al. Thin filament length in the cardiac sarcomere varies with sarcomere length but is independent of titin and nebulin. J Mol Cell Cardiol. 2016;97:286–94. doi: 10.1016/j.yjmcc.2016.04.013 27139341

49. Sieck GC. Design principles for life. Physiology (Bethesda). 2013;28(1):7–8. doi: 10.1152/physiol.00049.2012 23280352.

50. Sieck GC, Ferreira LF, Reid MB, Mantilla CB. Mechanical properties of respiratory muscles. Compr Physiol. 2013;3(4):1553–67. doi: 10.1002/cphy.c130003 24265238

51. Kiss B, Lee EJ, Ma W, Li FW, Tonino P, Mijailovich SM, et al. Nebulin stiffens the thin filament and augments cross-bridge interaction in skeletal muscle. Proc Natl Acad Sci U S A. 2018;115(41):10369–74. doi: 10.1073/pnas.1804726115 30249654

52. Zhang X, Kampourakis T, Yan Z, Sevrieva I, Irving M, Sun YB. Distinct contributions of the thin and thick filaments to length-dependent activation in heart muscle. Elife. 2017;6. doi: 10.7554/eLife.24081 28229860

53. Collibee SE, Bergnes G, Muci A, Browne WFt, Garard M, Hinken AC, et al. Discovery of Tirasemtiv, the First Direct Fast Skeletal Muscle Troponin Activator. ACS Med Chem Lett. 2018;9(4):354–8. doi: 10.1021/acsmedchemlett.7b00546 29670700

54. Lee EJ, De Winter JM, Buck D, Jasper JR, Malik FI, Labeit S, et al. Fast skeletal muscle troponin activation increases force of mouse fast skeletal muscle and ameliorates weakness due to nebulin-deficiency. PLoS One. 2013;8(2):e55861. doi: 10.1371/journal.pone.0055861 23437068

55. Ottenheijm CA, Buck D, de Winter JM, Ferrara C, Piroddi N, Tesi C, et al. Deleting exon 55 from the nebulin gene induces severe muscle weakness in a mouse model for nemaline myopathy. Brain. 2013;136(Pt 6):1718–31. doi: 10.1093/brain/awt113 23715096


Článek vyšel v časopise

PLOS One


2019 Číslo 11