Titin and diaphragm dysfunction in mechanically ventilated rats

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

Research output: Contribution to journalArticlepeer-review

33 Scopus citations


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 preincubation 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.

Original languageEnglish (US)
Pages (from-to)702-709
Number of pages8
JournalIntensive Care Medicine
Issue number4
StatePublished - Apr 2012


  • Diaphragm
  • Force
  • Mechanical ventilation
  • Myosin Titin
  • Single fiber

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine


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