Experimental

Intensive Care Medicine

, Volume 38, Issue 4, pp 702-709

First online:

Open Access This content is freely available online to anyone, anywhere at any time.

Titin and diaphragm dysfunction in mechanically ventilated rats

  • Hieronymus W. H. van HeesAffiliated withDepartment of Pulmonary Diseases, Radboud University Nijmegen Medical Centre
  • , Willem-Jan M. SchellekensAffiliated withDepartment of Anesthesiology, Radboud University Nijmegen Medical Centre
  • , Gilberto L. Andrade AcuñaAffiliated withDepartment of Pulmonary Diseases, Radboud University Nijmegen Medical Centre
  • , Marianne LinkelsAffiliated withDepartment of Pulmonary Diseases, Radboud University Nijmegen Medical Centre
  • , Theo HafmansAffiliated withDepartment of Pulmonary Diseases, Radboud University Nijmegen Medical Centre
  • , Coen A. C. OttenheijmAffiliated withDepartment of Molecular and Cellular Biology, University of Arizona
  • , Henk L. GranzierAffiliated withDepartment of Molecular and Cellular Biology, University of Arizona
  • , Gert-Jan SchefferAffiliated withDepartment of Anesthesiology, Radboud University Nijmegen Medical Centre
  • , Johannes G. van der HoevenAffiliated withDepartment of Intensive Care Medicine (631), Radboud University Nijmegen Medical Centre
    • , P. N. Richard DekhuijzenAffiliated withDepartment of Pulmonary Diseases, Radboud University Nijmegen Medical Centre
    • , Leo M. A. HeunksAffiliated withDepartment of Intensive Care Medicine (631), Radboud University Nijmegen Medical Centre Email author 

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.

Keywords

Mechanical ventilation Diaphragm Force Single fiber Myosin Titin