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Leaky ryanodine receptors contribute to diaphragmatic weakness during mechanical ventilation

Matecki, Stefan; Dridi, Haikel; Jung, Boris; Saint, Nathalie; Reiken, Steven R.; Scheuermann, Valérie; Mrozek, Ségolène; Santulli, Gaetano; Umanskaya, Alisa; Petrof, Basil J.; Jaber, Samir; Marks, Andrew R.; Lacampagne, Alain

Ventilator-induced diaphragmatic dysfunction (VIDD) refers to the diaphragm muscle weakness that occurs following prolonged controlled mechanical ventilation (MV). The presence of VIDD impedes recovery from respiratory failure. However, the pathophysiological mechanisms accounting for VIDD are still not fully understood. Here, we show in human subjects and a mouse model of VIDD that MV is associated with rapid remodeling of the sarcoplasmic reticulum (SR) Ca2+ release channel/ryanodine receptor (RyR1) in the diaphragm. The RyR1 macromolecular complex was oxidized, S-nitrosylated, Ser-2844 phosphorylated, and depleted of the stabilizing subunit calstabin1, following MV. These posttranslational modifications of RyR1 were mediated by both oxidative stress mediated by MV and stimulation of adrenergic signaling resulting from the anesthesia. We demonstrate in the murine model that such abnormal resting SR Ca2+ leak resulted in reduced contractile function and muscle fiber atrophy for longer duration of MV. Treatment with β-adrenergic antagonists or with S107, a small molecule drug that stabilizes the RyR1–calstabin1 interaction, prevented VIDD. Diaphragmatic dysfunction is common in MV patients and is a major cause of failure to wean patients from ventilator support. This study provides the first evidence to our knowledge of RyR1 alterations as a proximal mechanism underlying VIDD (i.e., loss of function, muscle atrophy) and identifies RyR1 as a potential target for therapeutic intervention.

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Title
Proceedings of the National Academy of Sciences
DOI
https://doi.org/10.1073/pnas.1609707113

More About This Work

Academic Units
Physiology and Cellular Biophysics
Published Here
October 7, 2016