Super-relaxed myosins contribute to respiratory muscle hibernation in mechanically ventilated patients.

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. Editor's summary: Many ventilated patients develop weakness of the diaphragm that can result in extubation failure; however, the underlying molecular mechanisms of this diaphragm weakness are incompletely understood. Here, van den Berg and colleagues studied diaphragm biopsies from ventilated patients in the intensive care unit and a rat model, finding that myofibers from these biopsies contained an increased proportion of myosins in the super-relaxed state, where the myosin head lies close to the thick filament backbone and does not bind to actin, leading to reduced contractility. In vitro, small-molecule troponin activators improved force generation in these myofibers, suggesting that targeting sarcomere proteins may be a potential treatment strategy for ventilator-associated diaphragm weakness. —Melissa L. Norton [ABSTRACT FROM AUTHOR]

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