The small-molecule fast skeletal troponin activator, CK-2127107, improves exercise tolerance in a rat model of heart failure

Journal of Pharmacology and Experimental Therapeutics

Volumn 353, Issue 1, 2015, Pages 159-168

  Hwee, Darren T ^a   Kennedy, Adam R ^a   Hartman, James J ^a   Ryans, Julie ^a   Durham, Nickie ^a   Malik, Fady I ^a   Jasper, Jeffrey R ^a  

^a Cytokinetics Inc   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 AMINOALKYL 5 N HETEROARYLPYRIMIDINE; AGENTS ACTING ON THE PERIPHERAL NERVOUS AND NEUROMUSCULAR SYSTEMS; CALCIUM; SARCOPLASMIC RETICULUM CALCIUM TRANSPORTING ADENOSINE TRIPHOSPHATASE; TROPONIN; UNCLASSIFIED DRUG; ADENOSINE TRIPHOSPHATASE (CALCIUM); PYRIMIDINE DERIVATIVE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BOVINE; CONTROLLED STUDY; DRUG BINDING; EXERCISE TOLERANCE; FEMALE; HEART FAILURE; HEART INFARCTION; MUSCLE FATIGUE; MUSCLE STRENGTH; MYOPATHY; NONHUMAN; PRIORITY JOURNAL; RABBIT; RAT; RAT MODEL; RUNNING; SINGLE DRUG DOSE; SKELETAL MUSCLE; SOLEUS MUSCLE; ANIMAL; COMPLICATION; DRUG EFFECTS; FAST MUSCLE FIBER; METABOLISM; MUSCLE CONTRACTION; MUSCLE FIBRIL; MUSCULAR ATROPHY; MYOCARDIAL INFARCTION; PATHOPHYSIOLOGY; ROTAROD TEST; SPRAGUE DAWLEY RAT; SYSTOLIC HEART FAILURE;

ANIMALS; CALCIUM; CALCIUM-TRANSPORTING ATPASES; CATTLE; FEMALE; HEART FAILURE, SYSTOLIC; MUSCLE CONTRACTION; MUSCLE FIBERS, FAST-TWITCH; MUSCLE, SKELETAL; MUSCULAR ATROPHY; MYOCARDIAL INFARCTION; MYOFIBRILS; PHYSICAL CONDITIONING, ANIMAL; PYRIMIDINES; RABBITS; RATS, SPRAGUE-DAWLEY; ROTAROD PERFORMANCE TEST; TROPONIN;

EID: 84928935578     PISSN: 00223565     EISSN: 15210103     Source Type: Journal    
DOI: 10.1124/jpet.114.222224     Document Type: Article

References (66)

1. Allen DG, Clugston E, Petersen Y, Röder IV, Chapman B, and Rudolf R (2011) Interactions between intracellular calcium and phosphate in intact mouse muscle during fatigue. J Appl Physiol (1985) 111:358-366.
2. Allen DG, Lamb GD, and Westerblad H (2008) Skeletal muscle fatigue: cellular mechanisms. Physiol Rev 88:287-332.
3. Anker SD, Ponikowski P, Varney S, Chua TP, Clark AL, Webb-Peploe KM, Harrington D, Kox WJ, Poole-Wilson PA, and Coats AJ (1997)Wasting as independent risk factor for mortality in chronic heart failure. Lancet 349:1050-1053.
4. Bauer TA, Wolff AA, Hirsch AT, Meng LL, Rogers K, Malik FI, and Hiatt WR (2014) Effect of tirasemtiv, a selective activator of the fast skeletal muscle troponin complex, in patients with peripheral artery disease. Vasc Med 19:297-306.
5. Blanchard EM and Solaro RJ (1984) Inhibition of the activation and troponin calcium binding of dog cardiac myofibrils by acidic pH. Circ Res 55:382-391.
6. Brooks GA, Fahey TD, Baldwin KM (2004) Exercise physiology: human bioenergetics and its applications, McGraw-Hill Higher Education, New York.
7. Bueno CR, Jr, Ferreira JC, Pereira MG, Bacurau AV, and Brum PC (2010) Aerobic exercise training improves skeletal muscle function and Ca21 handling-related protein expression in sympathetic hyperactivity-induced heart failure. J Appl Physiol (1985) 109:702-709.
8. Chin ER (2010) Intracellular Ca21 signaling in skeletal muscle: decoding a complex message. Exerc Sport Sci Rev 38:76-85.
9. Chin ER and Allen DG (1998) The contribution of pH-dependent mechanisms to fatigue at different intensities in mammalian single muscle fibres. J Physiol 512: 831-840.
10. Clark A, Rafferty D, and Arbuthnott K (1997) Relationship between isokinetic muscle strength and exercise capacity in chronic heart failure. Int J Cardiol 59:145-148.
11. De La Cruz EM and Ostap EM (2009) Kinetic and equilibrium analysis of the myosin ATPase. Methods Enzymol 455:157-192.
12. Delp MD, Duan C, Mattson JP, and Musch TI (1997) Changes in skeletal muscle biochemistry and histology relative to fiber type in rats with heart failure. J Appl Physiol (1985) 83:1291-1299.
13. Drexler H, Riede U, Münzel T, König H, Funke E, and Just H (1992) Alterations of skeletal muscle in chronic heart failure. Circulation 85:1751-1759.
14. Duscha BD, Kraus WE, Keteyian SJ, Sullivan MJ, Green HJ, Schachat FH, Pippen AM, Brawner CA, Blank JM, and Annex BH (1999) Capillary density of skeletal muscle: a contributing mechanism for exercise intolerance in class II-III chronic heart failure independent of other peripheral alterations. J Am Coll Cardiol 33: 1956-1963.
15. Ebashi S, Ebashi F, and Kodama A (1967) Troponin as the Ca11-receptive protein in the contractile system. J Biochem 62:137-138.
16. Gibbs JS, Keegan J, Wright C, Fox KM, and Poole-Wilson PA (1990) Pulmonary artery pressure changes during exercise and daily activities in chronic heart failure. J Am Coll Cardiol 15:52-61.
17. Gielen S, Sandri M, Kozarez I, Kratzsch J, Teupser D, Thiery J, Erbs S, Mangner N, Lenk K, Hambrecht R, et al. (2012) Exercise training attenuates MuRF-1 expression in the skeletal muscle of patients with chronic heart failure independent of age: the randomized Leipzig Exercise Intervention in Chronic Heart Failure and Aging catabolism study. Circulation 125:2716-2727.
18. Hansen R, Saikali KG, Chou W, Russell AJ, Chen MM, Vijayakumar V, Stoltz RR, Baudry S, Enoka RM, Morgans DJ, et al. (2014) Tirasemtiv amplifies skeletal muscle response to nerve activation in humans. Muscle Nerve 50:925-931.
19. Harrington D, Anker SD, Chua TP, Webb-Peploe KM, Ponikowski PP, Poole-Wilson PA, and Coats AJ (1997) Skeletal muscle function and its relation to exercise tolerance in chronic heart failure. J Am Coll Cardiol 30:1758-1764.
20. Harrington D and Coats AJ (1997) Skeletal muscle abnormalities and evidence for their role in symptom generation in chronic heart failure. Eur Heart J 18: 1865-1872.
21. Herrmann C, Sleep J, Chaussepied P, Travers F, and Barman T (1993) A structural and kinetic study on myofibrils prevented from shortening by chemical crosslinking. Biochemistry 32:7255-7263.
22. Hwee DT, Kennedy A, Ryans J, Russell AJ, Jia Z, Hinken AC, Morgans DJ, Malik FI, and Jasper JR (2014) Fast skeletal muscle troponin activator tirasemtiv increases muscle function and performance in the B6SJL-SOD1G93A ALS mouse model. PLoS ONE 9:e96921.
23. Kho AL, Perera S, Alexandrovich A, and Gautel M (2012a) The sarcomeric cytoskeleton as a target for pharmacological intervention. Curr Opin Pharmacol 12: 347-354.
24. Kho C, Lee A, and Hajjar RJ (2012b) Altered sarcoplasmic reticulum calcium cycling -targets for heart failure therapy. Nat Rev Cardiol 9:717-733.
25. Koh SG, Brenner DA, Korzick DH, Tickerhoof MM, Apstein CS, and Saupe KW (2003) Exercise intolerance during post-MI heart failure in rats: prevention with supplemental dietary propionyl-L-carnitine. Cardiovasc Drugs Ther 17:7-14.
26. Lee EJ, De Winter JM, Buck D, Jasper JR, Malik FI, Labeit S, Ottenheijm CA, and Granzier H (2013) Fast skeletal muscle troponin activation increases force of mouse fast skeletal muscle and ameliorates weakness due to nebulin-deficiency. PLoS ONE 8:e55861.
27. Lin SJ, McElfresh J, Hall B, Bloom R, and Farrell K (2012) Inspiratory muscle training in patients with heart failure: a systematic review. Cardiopulm Phys Ther J 23:29-36.
28. Lynch GS and Faulkner JA (1998) Contraction-induced injury to single muscle fibers: velocity of stretch does not influence the force deficit. Am J Physiol 275: C1548-C1554.
29. Malik FI, Hartman JJ, Elias KA, Morgan BP, Rodriguez H, Brejc K, Anderson RL, Sueoka SH, Lee KH, Finer JT, et al. (2011) Cardiac myosin activation: a potential therapeutic approach for systolic heart failure. Science 331:1439-1443.
30. Mancini DM, Coyle E, Coggan A, Beltz J, Ferraro N, Montain S, and Wilson JR (1989) Contribution of intrinsic skeletal muscle changes to 31P NMR skeletal muscle metabolic abnormalities in patients with chronic heart failure. Circulation 80:1338-1346.
31. Margossian SS and Lowey S (1982) Preparation of myosin and its subfragments from rabbit skeletal muscle. Methods Enzymol 85:55-71.
32. Massie B, Conway M, Yonge R, Frostick S, Ledingham J, Sleight P, Radda G, and Rajagopalan B (1987) Skeletal muscle metabolism in patients with congestive heart failure: relation to clinical severity and blood flow. Circulation 76:1009-1019.
33. Meyer FJ, Borst MM, Zugck C, Kirschke A, Schellberg D, Kübler W, and Haass M (2001) Respiratory muscle dysfunction in congestive heart failure: clinical correlation and prognostic significance. Circulation 103:2153-2158.
34. Middlekauff HR, Vigna C, Verity MA, Fonarow GC, Horwich TB, Hamilton MA, Shieh P, and Tupling AR (2012) Abnormalities of calcium handling proteins in skeletal muscle mirror those of the heart in humans with heart failure: a shared mechanism? J Card Fail 18:724-733.
35. Nosek TM, Fender KY, and Godt RE (1987) It is diprotonated inorganic phosphate that depresses force in skinned skeletal muscle fibers. Science 236:191-193.
36. Ochala J (2010) Ca21 sensitizers: An emerging class of agents for counterbalancing weakness in skeletal muscle diseases? Neuromuscul Disord 20:98-101.
37. Ottenheijm CA, Buck D, de Winter JM, Ferrara C, Piroddi N, Tesi C, Jasper JR, Malik FI, Meng H, Stienen GJ, et al. (2013) Deleting exon 55 from the nebulin gene induces severe muscle weakness in a mouse model for nemaline myopathy. Brain 136:1718-1731.
38. Pardee JD and Spudich JA (1982) Purification of muscle actin. Methods Enzymol 85: 164-181.
39. Perreault CL, Gonzalez-Serratos H, Litwin SE, Sun X, Franzini-Armstrong C, and Morgan JP (1993) Alterations in contractility and intracellular Ca21 transients in isolated bundles of skeletal muscle fibers from rats with chronic heart failure. Circ Res 73:405-412.
40. Pfeifer PC, Musch TI, and McAllister RM (2001) Skeletal muscle oxidative capacity and exercise tolerance in rats with heart failure. Med Sci Sports Exerc 33:542-548.
41. Piepoli MF, Guazzi M, Boriani G, Cicoira M, Corrà U, Dalla Libera L, Emdin M, Mele D, Passino C, Vescovo G, et al.; Working Group 'Exercise Physiology, Sport Cardiology and Cardiac Rehabilitation', Italian Society of Cardiology (2010b) Exercise intolerance in chronic heart failure: mechanisms and therapies. Part I. Eur J Cardiovasc Prev Rehabil 17:637-642.
42. Piepoli MF, Guazzi M, Boriani G, Cicoira M, Corrà U, Dalla Libera L, Emdin M, Mele D, Passino C, Vescovo G, et al.; Working Group 'Exercise Physiology, Sport Cardiology and Cardiac Rehabilitation', Italian Society of Cardiology (2010a) Exercise intolerance in chronic heart failure: mechanisms and therapies. Part II. Eur J Cardiovasc Prev Rehabil 17:643-648.
43. Piña IL, Apstein CS, Balady GJ, Belardinelli R, Chaitman BR, Duscha BD, Fletcher BJ, Fleg JL, Myers JN, and Sullivan MJ; American Heart Association Committee on exercise, rehabilitation, and prevention (2003) Exercise and heart failure: a statement from the American Heart Association Committee on exercise, rehabilitation, and prevention. Circulation 107:1210-1225.
44. Potter JD (1982) Preparation of troponin and its subunits. Methods Enzymol 85: 241-263.
45. Purdham DM, Rajapurohitam V, Zeidan A, Huang C, Gross GJ, and Karmazyn M (2008) A neutralizing leptin receptor antibody mitigates hypertrophy and hemodynamic dysfunction in the postinfarcted rat heart. Am J Physiol Heart Circ Physiol 295:H441-H446.
46. Ribeiro JP, Chiappa GR, and Callegaro CC (2012) The contribution of inspiratory muscles function to exercise limitation in heart failure: pathophysiological mechanisms. Rev Bras Fisioter 16:261-267.
47. Rosenfeld SS and Taylor EW (1985) Kinetic studies of calcium binding to regulatory complexes from skeletal muscle. J Biol Chem 260:252-261.
48. Rubin SA, Fishbein MC, and Swan HJ (1983) Compensatory hypertrophy in the heart after myocardial infarction in the rat. J Am Coll Cardiol 1:1435-1441.
49. Russell AJ, Hartman JJ, Hinken AC, Muci AR, Kawas R, Driscoll L, Godinez G, Lee KH, Marquez D, Browne WF, 4th, et al. (2012) Activation of fast skeletal muscle troponin as a potential therapeutic approach for treating neuromuscular diseases. Nat Med 18:452-455.
50. Schieffer B, Wollert KC, Berchtold M, Saal K, Schieffer E, Hornig B, Riede UN, and Drexler H (1995) Development and prevention of skeletal muscle structural alterations after experimental myocardial infarction. Am J Physiol 269: H1507-H1513.
51. Shefner J, Cedarbaum JM, Cudkowicz ME, Maragakis N, Lee J, Jones D, Watson ML, Mahoney K, Chen M, Saikali K, et al.; Neals/Cytokinetics Study Team (2012) Safety, tolerability and pharmacodynamics of a skeletal muscle activator in amyotrophic lateral sclerosis. Amyotroph Lateral Scler 13:430-438.
52. Simonini A, Chang K, Yue P, Long CS, and Massie BM (1999) Expression of skeletal muscle sarcoplasmic reticulum calcium-ATPase is reduced in rats with postinfarction heart failure. Heart 81:303-307.
53. Smillie LB (1982) Preparation and identification of alpha- and beta-tropomyosins. Methods Enzymol 85:234-241.
54. Solaro RJ, Pang DC, and Briggs FN (1971) The purification of cardiac myofibrils with Triton X-100. Biochim Biophys Acta 245:259-262.
55. Spudich JA and Watt S (1971) The regulation of rabbit skeletal muscle contraction. I. Biochemical studies of the interaction of the tropomyosin-troponin complex with actin and the proteolytic fragments of myosin. J Biol Chem 246:4866-4871.
56. Toth MJ, Shaw AO, Miller MS, VanBuren P, LeWinter MM, Maughan DW, and Ades PA (2010) Reduced knee extensor function in heart failure is not explained by inactivity. Int J Cardiol 143:276-282.
57. van Hees HW, Andrade Acuña G, Linkels M, Dekhuijzen PN, and Heunks LM (2011) Levosimendan improves calcium sensitivity of diaphragm muscle fibres from a rat model of heart failure. Br J Pharmacol 162:566-573.
58. van Hees HW, van der Heijden HF, Hafmans T, Ennen L, Heunks LM, Verheugt FW, and Dekhuijzen PN (2008) Impaired isotonic contractility and structural abnormalities in the diaphragm of congestive heart failure rats. Int J Cardiol 128:326-335.
59. Ward CW, Reiken S, Marks AR, Marty I, Vassort G, and Lacampagne A (2003) Defects in ryanodine receptor calcium release in skeletal muscle from postmyocardial infarct rats. FASEB J 17:1517-1519.
60. Westerblad H and Allen DG (1996) The effects of intracellular injections of phosphate on intracellular calcium and force in single fibres of mouse skeletal muscle. Pflugers Arch 431:964-970.
61. Wilson JR, Rayos G, Yeoh TK, Gothard P, and Bak K (1995) Dissociation between exertional symptoms and circulatory function in patients with heart failure. Circulation 92:47-53.
62. Winkelmann ER, Chiappa GR, Lima CO, Viecili PR, Stein R, and Ribeiro JP (2009) Addition of inspiratory muscle training to aerobic training improves cardiorespiratory responses to exercise in patients with heart failure and inspiratory muscle weakness. Am Heart J 158:768.e761-767.
63. Wong E, Selig S, and Hare DL (2011) Respiratory muscle dysfunction and training in chronic heart failure. Heart Lung Circ 20:289-294.
64. Yamaguchi F, Kawana K, Tanonaka K, Kamano I, Igarashi T, Gen E, Fujimoto Y, Maki T, Sanbe A, Nasa Y, et al. (1999) Improvement of exercise capacity of rats with chronic heart failure by long-term treatment with trandolapril. Br J Pharmacol 126:1585-1592.
65. Yang Z, Muci AR, Warrington J, Bergnes G, Morgan BP, Chuang C, Romero A, Collibee S, Qian X, and Lu PP (2011) inventors, Cytokinetics, Inc., assignee. Certain amino-pyrimidines, compositions thereof, and methods for their use. U.S. application WO 2011133888 A1. 2011 Oct 27.
66. Young OA and Davey CL (1981) Electrophoretic analysis of proteins from single bovine muscle fibres. Biochem J 195:317-327.