Differential regulation of proteolytic pathways in the diaphragm during mechanical ventilation

Mechanical ventilation (MV) during critical illness is associated with proteolysis and decreased protein synthesis, leading to ventilator-induced diaphragmatic dysfunction (VIDD) and intensive care unit - acquired weakness (ICU-AW). VIDD is associated with prolonged MV and weaning failure.

in this study, we aimed to identify a differential modulation between the diaphragm and other muscles during MV.

diaphragm and rectus abdominis muscle biopsies were obtained from 14 brain dead donors mechanically ventilated for at least 24 h. We performed histological analysis, RNA sequencing and explored pathways showing significant differential expression using RT-qPCR and Western blot.

The proteolytic and myogenic pathways were downregulated, whereas the inflammatory and extracellular matrix pathways were upregulated in the diaphragm in comparison to the rectus abdominis. We observed a relatively lower transcription of FOXO1 (-59 %), ubiquitin ligase Murf1 (-50 %) and protein kinase GSk3b (-90 %) in the diaphragm, whereas the CXCR-pi3k-akt pathway was upregulated. Myofiber cross-sectional areas were larger in the diaphragm than in rectus abdominis (2224-3934 μm² vs 2154-2973 μm², p = 0.012).

In the diaphragm of brain-dead donors mechanically ventilated for at least 24 h, atrophic muscle pathways are downregulated compared to the rectus abdominis. These results question the impact of MV on the diaphragm in critical illness and highlight the differential pathophysiology between ICU-AW and VIDD.