TY - JOUR
T1 - Leaky ryanodine receptors contribute to diaphragmatic weakness during mechanical ventilation
AU - Matecki, Stefan
AU - Dridi, Haikel
AU - Jung, Boris
AU - Saint, Nathalie
AU - Reiken, Steven R.
AU - Scheuermann, Valérie
AU - Mrozek, Ségolène
AU - Santulli, Gaetano
AU - Umanskaya, Alisa
AU - Petrof, Basil J.
AU - Jaber, Samir
AU - Marks, Andrew R.
AU - Lacampagne, Alain
N1 - Funding Information:
This work was supported by INSERM, Region Languedoc-Roussillon, Association Française contre les Myopathies, the Schaefer Foundation, Philippe Fundation, and the Canadian Institutes of Health Research. G.S. is supported by NIH Grant K99DK107895.
PY - 2016/8/9
Y1 - 2016/8/9
N2 - 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.
AB - 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.
KW - Beta adrenergic signaling
KW - Calcium
KW - Excitation-contraction coupling
KW - Skeletal muscle
KW - VIDD
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U2 - 10.1073/pnas.1609707113
DO - 10.1073/pnas.1609707113
M3 - Article
C2 - 27457930
AN - SCOPUS:84982953388
SN - 0027-8424
VL - 113
SP - 9069
EP - 9074
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 32
ER -