Super-relaxed myosins contribute to respiratory muscle hibernation in mechanically ventilated patients.
Marloes van den BergZhonghua ShiWout J ClaassenPleuni HooijmanChristopher T A LewisJesper Løvind AndersenRobbert J van der PijlSylvia J P BogaardsStefan ConijnEva L PetersLeon P L BegthelBas A UijterwijkJohan LindqvistPaul R LanglaisArmand R J GirbesSandra StapelHenk L GranzierKenneth S CampbellWeikang MaThomas C IrvingDarren T HweeJames J HartmanFady I MalikMarinus PaulAlbertus BeishuizenJulien OchalaLeo HeunksCoen A C OttenheijmPublished in: Science translational medicine (2024)
Patients receiving mechanical ventilation in the intensive care unit (ICU) frequently develop contractile weakness of the diaphragm. Consequently, they may experience difficulty weaning from mechanical ventilation, which increases mortality and poses a high economic burden. Because of a lack of knowledge regarding the molecular changes in the diaphragm, no treatment is currently available to improve diaphragm contractility. We compared diaphragm biopsies from ventilated ICU patients ( N = 54) to those of non-ICU patients undergoing thoracic surgery ( N = 27). By integrating data from myofiber force measurements, x-ray diffraction experiments, and biochemical assays with clinical data, we found that in myofibers isolated from the diaphragm of ventilated ICU patients, myosin is trapped in an energy-sparing, super-relaxed state, which impairs the binding of myosin to actin during diaphragm contraction. Studies on quadriceps biopsies of ICU patients and on the diaphragm of previously healthy mechanically ventilated rats suggested that the super-relaxed myosins are specific to the diaphragm and not a result of critical illness. Exposing slow- and fast-twitch myofibers isolated from the diaphragm biopsies to small-molecule compounds activating troponin restored contractile force in vitro. These findings support the continued development of drugs that target sarcomere proteins to increase the calcium sensitivity of myofibers for the treatment of ICU-acquired diaphragm weakness.
Keyphrases
- mechanical ventilation
- acute respiratory distress syndrome
- intensive care unit
- end stage renal disease
- extracorporeal membrane oxygenation
- respiratory failure
- ejection fraction
- chronic kidney disease
- newly diagnosed
- patients undergoing
- small molecule
- healthcare
- peritoneal dialysis
- skeletal muscle
- high throughput
- single molecule
- binding protein
- electronic health record
- risk factors
- patient reported outcomes
- high resolution
- smooth muscle
- cell migration
- deep learning
- data analysis
- artificial intelligence