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Open Access 01-04-2012 | Experimental

Titin and diaphragm dysfunction in mechanically ventilated rats

Authors: Hieronymus W. H. van Hees, Willem-Jan M. Schellekens, Gilberto L. Andrade Acuña, Marianne Linkels, Theo Hafmans, Coen A. C. Ottenheijm, Henk L. Granzier, Gert-Jan Scheffer, Johannes G. van der Hoeven, P. N. Richard Dekhuijzen, Leo M. A. Heunks

Published in: Intensive Care Medicine | Issue 4/2012

Abstract

Purpose

Diaphragm weakness induced by mechanical ventilation may contribute to difficult weaning from the ventilator. For optimal force generation the muscle proteins myosin and titin are indispensable. The present study investigated if myosin and titin loss or dysfunction are involved in mechanical ventilation-induced diaphragm weakness.

Methods

Male Wistar rats were either assigned to a control group (n = 10) or submitted to 18 h of mechanical ventilation (MV, n = 10). At the end of the experiment, diaphragm and soleus muscle were excised for functional and biochemical analysis.

Results

Maximal specific active force generation of muscle fibers isolated from the diaphragm of MV rats was lower than controls (128 ± 9 vs. 165 ± 13 mN/mm², p = 0.02) and was accompanied by a proportional reduction of myosin heavy chain concentration in these fibers. Passive force generation upon stretch was significantly reduced in diaphragm fibers from MV rats by ca. 35%. Yet, titin content was not significantly different between control and MV diaphragm. In vitro pre-incubation with phosphatase-1 decreased passive force generation upon stretch in diaphragm fibers from control, but not from MV rats. Mechanical ventilation did not affect active or passive force generation in the soleus muscle.

Conclusions

Mechanical ventilation leads to impaired diaphragm fiber active force-generating capacity and passive force generation upon stretch. Loss of myosin contributes to reduced active force generation, whereas reduced passive force generation is likely to result from a decreased phosphorylation status of titin. These impairments were not discernable in the soleus muscle of 18 h mechanically ventilated rats.

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Vassilakopoulos T (2008) Ventilator-induced diaphragm dysfunction: the clinical relevance of animal models. Intensive Care Med 34:7–16PubMedCrossRef

Vassilakopoulos T, Petrof BJ (2004) Ventilator-induced diaphragmatic dysfunction. Am J Respir Crit Care Med 169:336–341PubMedCrossRef

Vassilakopoulos T, Zakynthinos S, Roussos C (1998) The tension-time index and the frequency/tidal volume ratio are the major pathophysiologic determinants of weaning failure and success. Am J Respir Crit Care Med 158:378–385PubMed

Harikumar G, Egberongbe Y, Nadel S, Wheatley E, Moxham J, Greenough A et al (2009) Tension-time index as a predictor of extubation outcome in ventilated children. Am J Respir Crit Care Med 180:982–988PubMedCrossRef

Heunks LM, van der Hoeven JG (2010) Clinical review: the ABC of weaning failure–a structured approach. Crit Care 14:245PubMedCrossRef

Levine S, Nguyen T, Taylor N, Friscia ME, Budak MT, Rothenberg P, Zhu J, Sachdeva R, Sonnad S, Kaiser LR, Rubinstein NA, Powers SK, Shrager JB (2008) Rapid disuse atrophy of diaphragm fibers in mechanically ventilated humans. N Engl J Med 358:1327–1335PubMedCrossRef

Shanely RA, Zergeroglu MA, Lennon SL, Sugiura T, Yimlamai T, Enns D, Belcastro A, Powers SK (2002) Mechanical ventilation-induced diaphragmatic atrophy is associated with oxidative injury and increased proteolytic activity. Am J Respir Crit Care Med 166:1369–1374PubMedCrossRef

Jaber S, Petrof BJ, Jung B, Chanques G, Berthet JP, Rabuel C, Bouyabrine H, Courouble P, Koechlin-Ramonatxo C, Sebbane M, Similowski T, Scheuermann V, Mebazaa A, Capdevila X, Mornet D, Mercier J, Lacampagne A, Philips A, Matecki S (2011) Rapidly progressive diaphragmatic weakness and injury during mechanical ventilation in humans. Am J Respir Crit Care Med 183:364–371PubMedCrossRef

Sassoon CS, Caiozzo VJ, Manka A, Sieck GC (2002) Altered diaphragm contractile properties with controlled mechanical ventilation. J Appl Physiol 92:2585–2595PubMed

10.

Le Bourdelles G, Viires N, Boczkowski J, Seta N, Pavlovic D, Aubier M (1994) Effects of mechanical ventilation on diaphragmatic contractile properties in rats. Am J Respir Crit Care Med 149:1539–1544PubMed

11.

Powers SK, Shanely RA, Coombes JS, Koesterer TJ, McKenzie M, Van Gammeren D, Cicale M, Dodd SL (2002) Mechanical ventilation results in progressive contractile dysfunction in the diaphragm. J Appl Physiol 92:1851–1858PubMed

12.

Maes K, Testelmans D, Powers S, Decramer M, Gayan-Ramirez G (2007) Leupeptin inhibits ventilator-induced diaphragm dysfunction in rats. Am J Respir Crit Care Med 175:1134–1138PubMedCrossRef

13.

Brenner B (1998) Muscle mechanics II: skinned muscle fibers. In: Sugi H (ed) Current methods in muscle physiology. Oxford University Press, New York, pp 33–69

14.

Geiger PC, Cody MJ, Macken RL, Sieck GC (2000) Maximum specific force depends on myosin heavy chain content in rat diaphragm muscle fibers. J Appl Physiol 89:695–703PubMed

15.

Bernard N, Matecki S, Py G, Lopez S, Mercier J, Capdevila X (2003) Effects of prolonged mechanical ventilation on respiratory muscle ultrastructure and mitochondrial respiration in rabbits. Intensive Care Med 29:111–118PubMed

16.

Horwich TB, Patel J, Maclellan WR, Fonarow GC (2003) Cardiac troponin I is associated with impaired hemodynamics, progressive left ventricular dysfunction, and increased mortality rates in advanced heart failure. Circulation 108:833–838PubMedCrossRef

17.

Horowits R, Kempner ES, Bisher ME, Podolsky RJ (1986) A physiological role for titin and nebulin in skeletal muscle. Nature 323:160–164PubMedCrossRef

18.

Granzier H, Labeit S (2007) Structure-function relations of the giant elastic protein titin in striated and smooth muscle cells. Muscle Nerve 36:740–755PubMedCrossRef

19.

Udaka J, Ohmori S, Terui T, Ohtsuki I, Ishiwata S, Kurihara S, Fukuda N (2008) Disuse-induced preferential loss of the giant protein titin depresses muscle performance via abnormal sarcomeric organization. J Gen Physiol 131:33–41PubMedCrossRef

20.

Ottenheijm CA, Granzier H (2010) Role of titin in skeletal muscle function and disease. Adv Exp Med Biol 682:105–122PubMedCrossRef

21.

Ottenheijm CA, Heunks LM, Hafmans T, van der Ven PF, Benoist C, Zhou H, Labeit S, Granzier HL, Dekhuijzen PN (2006) Titin and diaphragm dysfunction in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 173:527–534PubMedCrossRef

22.

van Hees HW, Ottenheijm CA, Granzier HL, Dekhuijzen PN, Heunks LM (2010) Heart failure decreases passive tension generation of rat diaphragm fibers. Int J Cardiol 141:275–283PubMedCrossRef

23.

Hidalgo C, Hudson B, Bogomolovas J, Zhu Y, Anderson B, Greaser M, Labeit S, Granzier H (2009) PKC phosphorylation of titin’s PEVK element: a novel and conserved pathway for modulating myocardial stiffness. Circ Res 105(631–8):17

24.

van Hees HW, van der Heijden HF, Ottenheijm CA, Heunks LM, Pigmans CJ, Verheugt FW, Brouwer RM, Dekhuijzen PN (2007) Diaphragm single-fiber weakness and loss of myosin in congestive heart failure rats. Am J Physiol Heart Circ Physiol 293:H819–H828PubMedCrossRef

25.

Ochala J, Radell PJ, Eriksson LI, Larsson L (2010) EMD 57033 partially reverses ventilator-induced diaphragm muscle fibre calcium desensitisation. Pflugers Arch 459:475–483PubMedCrossRef

26.

Levine S, Biswas C, Dierov J, Barsotti R, Shrager JB, Nguyen T, Sonnad S, Kucharchzuk JC, Kaiser LR, Singhal S, Budak MT (2011) Increased proteolysis, myosin depletion, and atrophic AKT-FOXO signaling in human diaphragm disuse. Am J Respir Crit Care Med 183:483–490PubMedCrossRef

27.

Ottenheijm CA, Heunks LM, Sieck GC, Zhan WZ, Jansen SM, Degens H, de Boo T, Dekhuijzen PN (2005) Diaphragm dysfunction in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 172:200–205PubMedCrossRef

28.

van Hees HW, Dekhuijzen PN, Heunks LM (2009) Levosimendan enhances force generation of diaphragm muscle from patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 179:41–47PubMedCrossRef

29.

Shanely RA, Van Gammeren D, Deruisseau KC, Zergeroglu AM, McKenzie MJ, Yarasheski KE, Powers SK (2004) Mechanical ventilation depresses protein synthesis in the rat diaphragm. Am J Respir Crit Care Med 170:994–999PubMedCrossRef

30.

Hussain SN, Mofarrahi M, Sigala I, Kim HC, Vassilakopoulos T, Maltais F, Bellenis I, Chaturvedi R, Gottfried SB, Metrakos P, Danialou G, Matecki S, Jaber S, Petrof BJ, Goldberg P (2010) Mechanical ventilation-induced diaphragm disuse in humans triggers autophagy. Am J Respir Crit Care Med 182:1377–1386PubMedCrossRef

31.

McClung JM, Kavazis AN, DeRuisseau KC, Falk DJ, Deering MA, Lee Y, Sugiura T, Powers SK (2007) Caspase-3 regulation of diaphragm myonuclear domain during mechanical ventilation-induced atrophy. Am J Respir Crit Care Med 175:150–159PubMedCrossRef

32.

LeWinter MM, Granzier H (2010) Cardiac titin: a multifunctional giant. Circulation 121:2137–2145PubMedCrossRef

33.

Labeit D, Watanabe K, Witt C, Fujita H, Wu Y, Lahmers S, Funck T, Labeit S, Granzier H (2003) Calcium-dependent molecular spring elements in the giant protein titin. Proc Natl Acad Sci U S A 100:13716–13721PubMedCrossRef

34.

Pierno S, Desaphy JF, Liantonio A, De Luca A, Zarrilli A, Mastrofrancesco L, Procino G, Valenti G, Conte Camerino D (2007) Disuse of rat muscle in vivo reduces protein kinase C activity controlling the sarcolemma chloride conductance. J Physiol 584:983–995PubMedCrossRef

35.

Lange S, Xiang F, Yakovenko A, Vihola A, Hackman P, Rostkova E, Kristensen J, Brandmeier B, Franzen G, Hedberg B, Gunnarsson LG, Hughes SM, Marchand S, Sejersen T, Richard I, Edström L, Ehler E, Udd B, Gautel M (2005) The kinase domain of titin controls muscle gene expression and protein turnover. Science 308:1599–1603PubMedCrossRef

36.

Puchner EM, Alexandrovich A, Kho AL, Hensen U, Schäfer LV, Brandmeier B, Gräter F, Grubmüller H, Gaub HE, Gautel M (2008) Mechanoenzymatics of titin kinase. Proc Natl Acad Sci U S A 105:13385–13390PubMedCrossRef

37.

Ottenheijm CA, van Hees HW, Heunks LM, Granzier H (2011) Titin-based mechanosensing and signaling: role in diaphragm atrophy during unloading? Am J Physiol Lung Cell Mol Physiol 300:L161–L166PubMedCrossRef

38.

Boles JM, Bion J, Connors A, Herridge M, Marsh B, Melot C, Pearl R, Silverman H, Stanchina M, Vieillard-Baron A, Welte T (2007) Weaning from mechanical ventilation. Eur Respir J 29:1033–1056PubMedCrossRef

39.

Sassoon CS, Zhu E, Caiozzo VJ (2004) Assist-control mechanical ventilation attenuates ventilator-induced diaphragmatic dysfunction. Am J Respir Crit Care Med 170:626–632PubMedCrossRef

40.

Papazian L, Forel JM, Gacouin A, Penot-Ragon C, Perrin G, Loundou A, Jaber S, Arnal JM, Perez D, Seghboyan JM, Constantin JM, Courant P, Lefrant JY, Guérin C, Prat G, Morange S, Roch A, ACURASYS Study Investigators (2010) Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med 363:1107–1116PubMedCrossRef

Title: Titin and diaphragm dysfunction in mechanically ventilated rats
Authors: Hieronymus W. H. van Hees
Willem-Jan M. Schellekens
Gilberto L. Andrade Acuña
Marianne Linkels
Theo Hafmans
Coen A. C. Ottenheijm
Henk L. Granzier
Gert-Jan Scheffer
Johannes G. van der Hoeven
P. N. Richard Dekhuijzen
Leo M. A. Heunks
Publication date: 01-04-2012
Publisher: Springer-Verlag
Published in: Intensive Care Medicine / Issue 4/2012
Print ISSN: 0342-4642
Electronic ISSN: 1432-1238
DOI: https://doi.org/10.1007/s00134-012-2504-5

At a glance: The STEP trials

Springer Medicine

Titin and diaphragm dysfunction in mechanically ventilated rats

Abstract

Purpose

Methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

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