Titin and diaphragm dysfunction in mechanically ventilated rats.
OBJECTIVE
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/mm(2), 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.
Department of Pulmonary Diseases, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Hieronymus W H
HW
van Hees
Willem-Jan M
WJ
Schellekens
Gilberto L
GL
Andrade Acuña
Marianne
M
Linkels
Theo
T
Hafmans
Coen A C
CA
Ottenheijm
Henk L
HL
Granzier
Gert-Jan
GJ
Scheffer
Johannes G
JG
van der Hoeven
P N Richard
PN
Dekhuijzen
Leo M A
LM
Heunks
D000818:Animals; D064211:Connectin; D003964:Diaphragm / Q000503:physiopathology*; D004195:Disease Models, Animal; D008297:Male; D009124:Muscle Proteins / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000503:physiopathology*; D009218:Myosins / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012121:Respiration, Artificial / Q000009:adverse effects*; D015300:Ventilator Weaning
D064211:Connectin; D009124:Muscle Proteins; D011494:Protein Kinases; D009218:Myosins