Abstract
Mechanical ventilation (MV) is a life-saving intervention for many critically ill patients. Unfortunately, prolonged MV results in the rapid development of diaphragmatic atrophy and weakness. Importantly, endurance exercise training results in a diaphragmatic phenotype that is protected against ventilator-induced diaphragmatic atrophy and weakness. The mechanisms responsible for this exercise-induced protection against ventilator-induced diaphragmatic atrophy remain unknown. Therefore, to investigate exercise-induced changes in diaphragm muscle proteins, we compared the diaphragmatic proteome from sedentary and exercise-trained rats. Specifically, using label-free liquid chromatography-mass spectrometry, we performed a proteomics analysis of both soluble proteins and mitochondrial proteins isolated from diaphragm muscle. The total number of diaphragm proteins profiled in the soluble protein fraction and mitochondrial protein fraction were 813 and 732, respectively. Endurance exercise training significantly (P<0.05, FDR <10%) altered the abundance of 70 proteins in the soluble diaphragm proteome and 25 proteins of the mitochondrial proteome. In particular, key cytoprotective proteins that increased in relative abundance following exercise training included mitochondrial fission process 1 (Mtfp1; MTP18), 3-mercaptopyruvate sulfurtransferase (3MPST), microsomal glutathione S-transferase 3 (Mgst3; GST-III), and heat shock protein 70 kDa protein 1A/1B (HSP70). While these proteins are known to be cytoprotective in several cell types, the cyto-protective roles of these proteins have yet to be fully elucidated in diaphragm muscle fibers. Based upon these important findings, future experiments can now determine which of these diaphragmatic proteins are sufficient and/or required to promote exercise-induced protection against inactivity-induced muscle atrophy.
Highlights
Maintaining skeletal muscle mass is important for protecting health and sustaining the quality of life
The integrity of our isolation protocol was verified by measuring mitochondrial coupling using the respiratory control ratio (RCR; state 3 respiration divided by state 4 respiration; CON: RCR = 6.3±0.2; exercise training (EX): RCR = 6.4±0.4)
Using state-of-the-art proteomics techniques, this investigation is the first study to catalogue the protein abundance changes that occur in the diaphragm following endurance exercise training and is the most comprehensive profiling of diaphragm muscle to date
Summary
Maintaining skeletal muscle mass is important for protecting health and sustaining the quality of life. Prolonged periods of muscular inactivity (e.g., limb immobilization, bed rest, or mechanical ventilation) leads to a decrease in muscle mass (i.e., atrophy) and muscle weakness [1]. Of the many forms of disuse muscle atrophy, prolonged mechanical ventilation (MV) is one of the most unique [2]. VIDD is important because diaphragmatic weakness is predicted to be an important contributory factor in the inability to remove patients (i.e. wean) from the ventilator [5]. Difficult weaning leads to prolonged hospitalization along with increased patient morbidity and mortality [6]; preventing problems in weaning patients from the ventilator is important. No established clinical therapy exists to prevent VIDD and developing an intervention to protect against VIDD is imperative
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