ABSTRACT Introduction/Aims In dystrophic mice ( mdx , a genetic homolog of Duchenne muscular dystrophy: DMD), previous studies showed that mechanical ventilation (MV) induces ventilator‐induced diaphragmatic dysfunction (VIDD). However, susceptibility to mechanical stress caused by asynchrony remains unknown. Our aims were to investigate whether MV exacerbates diaphragm vulnerability to eccentric stress and to evaluate the role of RyR1 remodeling and NOX2 activation. Methods Male mdx and wild‐type (WT) mice (10–12 weeks) were assigned to non‐ventilated or 6‐h MV groups. Diaphragm strength and susceptibility to eccentric contractions mimicking asynchrony were assessed, along with remodeling of the Ca 2+ release channel RyR1. Two preventive strategies were tested: in vivo S107 treatment (RyR1‐stabilizing compound) administered before MV; and in vitro incubation of diaphragms previously ventilated with S107 or ebselen (NOX2 inhibitor) just before eccentric stress. Results MV reduced maximal tetanic force by 20.1% in WT and 27.0% in mdx mice without sarcolemmal injury. In mdx mice MV significantly increased susceptibility to eccentric contraction, causing a 45% greater force deficit and increased sarcolemmal damage. Pretreatment with S107 prevented both MV‐induced weakness and eccentric stress susceptibility. After 6 h MV, incubation with S107 or ebselen mitigated susceptibility to eccentric contraction. RyR1 oxidation, phosphorylation, and calstabin1 dissociation induced by MV were exacerbated by eccentric stress; S107 preserved calstabin1 binding, while ebselen reduced RyR1 oxidative modifications. Discussion MV exacerbates diaphragm vulnerability to mechanical stress in dystrophin‐deficient muscle through RyR1 remodeling and NOX2 activation. Preventing asynchrony and targeting RyR1 or NOX2 may represent therapeutic strategies to limit respiratory complications in DMD.
- Asynchrony Related to Mechanical Ventilation Exacerbates Diaphragm Dysfunction in a Mouse Model of Duchenne Muscular Dystrophy
- Mohamad Yehya - Université de Montpellier, PhyMedExp - Physiologie et Médecine Expérimentale du coeur et des musclesHaikel Dridi - Columbia UniversityEric Estève - Université de Montpellier, PhyMedExp - Physiologie et Médecine Expérimentale du coeur et des musclesJohan Moreau - Université de Montpellier, PhyMedExp - Physiologie et Médecine Expérimentale du coeur et des musclesSteven Reiken - Columbia UniversityAndrew Marks - Columbia UniversityAlain Lacampagne - Université de Montpellier, PhyMedExp - Physiologie et Médecine Expérimentale du coeur et des musclesStefan Matecki - Université de Montpellier, PhyMedExp - Physiologie et Médecine Expérimentale du coeur et des muscles
- Muscle & Nerve
- 99230802009311
- PhyMedExp - Physiologie et Médecine Expérimentale du coeur et des muscles
- English
- Journal article
- hal-05602747