Is Mitochondrial Oxidative Stress the Key Contributor to Diaphragm Atrophy and Dysfunction in Critically Ill Patients?

Abstract

Diaphragm dysfunction is prevalent in the progress of respiratory dysfunction in various critical illnesses. Respiratory muscle weakness may result in insufficient ventilation, coughing reflection suppression, pulmonary infection, and difficulty in weaning off respirators. All of these further induce respiratory dysfunction and even threaten the patients’ survival. The potential mechanisms of diaphragm atrophy and dysfunction include impairment of myofiber protein anabolism, enhancement of myofiber protein degradation, release of inflammatory mediators, imbalance of metabolic hormones, myonuclear apoptosis, autophagy, and oxidative stress. Among these contributors, mitochondrial oxidative stress is strongly implicated to play a key role in the process as it modulates diaphragm protein synthesis and degradation, induces protein oxidation and functional alteration, enhances apoptosis and autophagy, reduces mitochondrial energy supply, and is regulated by inflammatory cytokines via related signaling molecules. This review aims to provide a concise overview of pathological mechanisms of diaphragmatic dysfunction in critically ill patients, with special emphasis on the role and modulating mechanisms of mitochondrial oxidative stress.

Diaphragmatic thickening fraction as a potential predictor of response to continuous positive airway pressure ventilation in Covid-19 pneumonia: A single-center pilot study

“…( Xia et al, 2019 ) However, several studies have shown that oxidative mechanisms, mitochondrial impairment, and cytokine action (including interleukin 6 and tumor-necrosis factor α) contribute together determining the activation of catabolic processes of the diaphragm. ( Duan and Bai, 2020 ) From the data in our possession, we cannot correlate the degree of aeration or the plasma cytokine levels to support the respiratory muscle load. Further studies in this direction would be required.…”

“…Indeed, diaphragmatic dysfunction has ben reported in a large proportion of critically ill patients at the time of ICU admission ( Demoule et al, 2013 ) and possibly associated with early multi-organ dysfunction ( Ricoy et al, 2019 ; Vetrugno et al, 2019 ) and alteration of mitochondrial function. ( Duan and Bai, 2020 )…”

Respiratory Sarcopenia and Sarcopenic Respiratory Disability: Concepts, Diagnosis, and Treatment

“…Endotoxin induces weakening of the diaphragm through the activation of caspase 3 in the diaphragm ( 48 ). Also, in the process promoting protein catalysis, the oxidative stress of mitochondria is associated with diaphragm atrophy and induced dysfunction in patients with severe infection ( 49 ). Inflammation of the respiratory muscles becomes a promoter of respiratory sarcopenia, which can then be one of the factors causing respiratory dysfunction.…”

Mechanical ventilation preserves diaphragm mitochondrial function in a rat sepsis model

“…Even though IL-1β may induce diaphragm weakness without any oxidative stress [ 35 ], our data along with previous findings [ 15 , 19 , 21 , 38 ] suggest that the intra-diaphragmatic upregulation of IL-1β mRNA leads to an increase in oxidative and nitrosative stress, possibly linked to the stimulation of iNOS and inhibition of mitochondrial respiration and ATP generation [ 36 , 37 ]. With regard to those studies, we suggested that the early IL-1β mRNA activation would trigger diaphragm dysfunction through its negative effect upon mitochondrial function and ROS generation [ 4 ]. We confirmed here that CLP impaired diaphragm mitochondrial respiration and ATP production in the early stages of septic disease.…”

“…Several mechanisms could explain contractile dysfunction of diaphragm muscle during sepsis [ 3 ]. Mitochondrial dysfunction and oxidative stress that lead to diaphragm protein degradation and muscle atrophy have been proposed [ 4 ]. In the septic diaphragm, spontaneous contractions that persist to sustain respiration potentially aggravate the injuries induced by oxidative and nitrosative stress [ 5 ].…”