Abstract
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.
| Original language | English |
|---|---|
| Article number | eadg3894 |
| Journal | Science Translational Medicine |
| Volume | 16 |
| Issue number | 758 |
| DOIs | |
| State | Published - Jul 31 2024 |
Bibliographical note
Publisher Copyright:Copyright © 2024 The Authors, some rights reserved.
Funding
Acknowledgments: We wish to thank all the patients who participated in the study. Funding: This work was supported by nhlBi grant hl-121500 (c.a.c.o.); ZonMW grant 09120011910004 (c.a.c.o. and l.h.); Medical research council UK (Mr/S023593/1) and lundbeck Foundation grant r434-2023-311 (J.o.); nhlBi grant hl-146676 (K.S.c.); and nhlBi grant r35hl144998 (h.G.). This study used resources of the advanced Photon Source, a US department of energy (doe) office of Science User Facility, operated for the doe office of Science by argonne national laboratory under contract no. de-ac02-06ch11357. BiocaT was supported by grant P30 GM138395 from the national institute of General Medical Sciences of the national institutes of health. Author contributions: c.a.c.o. and l.h. designed the study. M.v.B., Z.S., W.J.c., and P.h. were responsible for sample collection processing. M.v.B., Z.S., W.J.c., P.h., c.T.a.l., J.l.a., r.J.P., S.J.P.B., S.c., e.l.P., l.P.l.B., B.U., J.l., P.r.l., K.S.c., W.M., T.i., d.T.h., J.J.h., and F.i.M. performed experiments in the laboratory. S.S., M.P., a.B., a.r.J.G., and l.h. were responsible for patient recruitment. M.v.B., Z.S., and W.J.c. were responsible for data collection and management. M.v.B., Z.S., and W.J.c. performed statistical analysis and created figures. M.v.B., Z.S., W.J.c., and c.a.c.o. drafted the manuscript. M.v.B., Z.S., W.J.c., J.o., l.h., h.G., and c.a.c.o. critically revised the manuscript. all authors read and approved the final manuscript. Competing interests: J.J.h., d.T.h., and F.i.M. are employees of cytokinetics and were financially compensated for their work. l.h. has received consulting fees from liberate Medical (USa) and Pulmotech (nl). l.h. has received a speaker/travel fee from Mindray. W.M. consults for edgewise Therapeutics inc. The other authors declare that they have no competing interests. Data and materials availability: all data associated with this study are present in the paper or the Supplementary Materials. requests for deidentified patient data by academic investigators will be handled by the respective institutions through a data transfer agreement. We wish to thank all the patients who participated in the study. Funding: This work was supported by NHLBI grant HL-121500 (C.A.C.O.); ZonMW grant 09120011910004 (C.A.C.O. and L.H.); Medical Research Council UK (MR/S023593/1) and Lundbeck Foundation grant R434-2023-311 (J.O.); NHLBI grant HL-146676 (K.S.C.); and NHLBI grant R35HL144998 (H.G.). This study used resources of the Advanced Photon Source, a US Department of Energy (DOE) Office of Science User Facility, operated for the DOE Office of Science by Argonne National Laboratory under contract no. DE-AC02-06CH11357. BioCAT was supported by grant P30 GM138395 from the National Institute of General Medical Sciences of the National Institutes of Health.
| Funders | Funder number |
|---|---|
| National Institute of General Medical Sciences DP2GM119177 Sophie Dumont National Institute of General Medical Sciences | |
| National Institutes of Health (NIH) | |
| U.S. Department of Energy | |
| Office of Science Programs | |
| UK Medical Research Council, Engineering and Physical Sciences Research Council | Mr/S023593/1 |
| Lundbeck Foundation Initiative for Integrative Psychiatric Research | R35HL144998, hl-146676, r434-2023-311 |
| Argonne National Laboratory | P30 GM138395, DE-AC02-06CH11357 |
| National Heart, Lung, and Blood Institute (NHLBI) | HL-121500 |
| ZonMw Memorabel | 09120011910004 |
ASJC Scopus subject areas
- General Medicine
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