Τίτλος:
Mechanical Ventilation-induced Diaphragm Disuse in Humans Triggers
Autophagy
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Rationale: Controlled mechanical ventilation (CMV) results in atrophy of
the human diaphragm. The autophagy-lysosome pathway (ALP) contributes to
skeletal muscle proteolysis, but its contribution to diaphragmatic
protein degradation in mechanically ventilated patients is unknown.
Objectives: To evaluate the autophagy pathway responses to CMV in the
diaphragm and limb muscles of humans and to identify the roles of FOXO
transcription factors in these responses.
Methods: Muscle biopsies were obtained from nine control subjects and
nine brain-dead organ donors. Subjects were mechanically ventilated for
2 to 4 hours and 15 to 276 hours, respectively. Activation of the
ubiquitin-proteasome system was detected by measuring mRNA expressions
of Atrogin-1, MURF1, and protein expressions of UBC2, UBC4, and the
alpha subunits of the 20S proteasome (MCP231). Activation of the ALP was
detected by electron microscopy and by measuring the expressions of
several autophagy-related genes. Total carbonyl content and HNE-protein
adduct formation were measured to assess oxidative stress. Total AKT,
phosphorylated and total FOXO1, and FOXO3A protein levels were also
measured.
Measurements and Main Results: Prolonged CMV triggered activation of the
ALP as measured by the appearance of autophagosomes in the diaphragm and
increased expressions of autophagy-related genes, as compared with
controls. Induction of autophagy was associated with increased protein
oxidation and enhanced expression of the FOXO1 gene, but not the FOXO3A
gene. CMV also triggered the inhibition of both AKT expression and FOXO1
phosphorylation. Conclusions: We propose that prolonged CMV causes
diaphragm disuse, which, in turn, leads to activation of the ALP through
oxidative stress and the induction of the FOXO1 transcription factor.
Συγγραφείς:
Hussain, Sabah N. A.
Mofarrahi, Mahroo
Sigala, Ioanna
Kim,
Ho Cheol
Vassilakopoulos, Theodoros
Maltais, Francois and
Bellenis, Ion
Chaturvedi, Rakesh
Gottfried, Stewart B. and
Metrakos, Peter
Danialou, Gawiyou
Matecki, Stefan
Jaber,
Samir
Petrof, Basil J.
Goldberg, Peter
Περιοδικό:
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
Εκδότης:
AMER THORACIC SOC
Λέξεις-κλειδιά:
proteasome; oxidative stress; FOXO proteins; AKT; skeletal muscles
DOI:
10.1164/rccm.201002-0234OC
