Background: Ventilator-induced diaphragmatic dysfunction (VIDD) significantly affects the prognosis of critically ill patients and has attracted considerable attention. Tripartite motif-containing protein 63 (TRIM63) plays a pivotal role in muscle protein degradation and muscle mass regulation. Its overexpression is closely associated with VIDD; however, data on the specific effects of TRIM63 on this pathological process remain insufficient.
Objectives: The aim of this study is to elucidate the role of TRIM63 in VIDD and to assess the correlation between the TRIM63-peroxisome proliferator activated receptor α (PPARα)/PPAR gamma coactivator (PGC-1α) pathway and mitochondrial function.
Methods: Specific pathogen-free grade female Wistar rats were divided into four groups: Sham + NS, Sham + MyoMed-205, MV + NS, and MV + MyoMed-205. The inhibitor group received MyoMed-205 to suppress the expression of TRIM63. After the experiment, diaphragmatic contractility, mitochondrial structure and function, oxidative stress levels, autophagy, apoptosis, and the involvement of the PPARα/PGC-1α pathway were evaluated.
Results: Our findings indicated that inhibiting TRIM63 prevented mechanical ventilation (MV)-induced diaphragmatic contractile dysfunction and atrophy. Mechanistically, inhibition of the expression of TRIM63 resulted in significant upregulation of the PPARα and PGC-1α expression levels, improved mitochondrial dynamics, enhanced the mitochondrial membrane potential, and reduced mitophagy and apoptosis. Structurally, inhibition of the expression of TRIM63 ameliorated MV-induced mitochondrial fragmentation, fusion, and fission.
Conclusions: The upregulated expression of TRIM63 in VIDD exacerbated mitochondrial damage by inhibiting the PPARα/PGC-1α signaling pathway, leading to increased reactive oxygen species, mitophagy, and apoptosis. Inhibition of the expression of TRIM63 enhanced mitochondrial function, decreased mitophagy and apoptosis, and mitigated VIDD. Thus, TRIM63 may serve as a potential target for the prevention and treatment of VIDD.
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