calpain and Critical-Illness

To review current knowledge about the impact of prolonged mechanical ventilation on diaphragmatic function and biology.. Systematic literature review.. Prolonged mechanical ventilation can promote diaphragmatic atrophy and contractile dysfunction. As few as 18 hrs of mechanical ventilation results in diaphragmatic atrophy in both laboratory animals and humans. Prolonged mechanical ventilation is also associated with diaphragmatic contractile dysfunction. Studies using animal models revealed that mechanical ventilation-induced diaphragmatic atrophy is due to increased diaphragmatic protein breakdown and decreased protein synthesis. Recent investigations have identified calpain, caspase-3, and the ubiquitin-proteasome system as key proteases that contribute to mechanical ventilation-induced diaphragmatic proteolysis. The scientific challenge for the future is to delineate the mechanical ventilation-induced signaling pathways that activate these proteases and depress protein synthesis in the diaphragm. Future investigations that define the signaling mechanisms responsible for mechanical ventilation-induced diaphragmatic weakness will provide the knowledge required for the development of new medicines that can maintain diaphragmatic mass and function during prolonged mechanical ventilation.

Topics: Animals; Antioxidants; Calpain; Caspase 3; Critical Illness; Diaphragm; Enzyme Inhibitors; Humans; Muscle Contraction; Muscular Atrophy; Proteasome Endopeptidase Complex; Respiration, Artificial; Risk Factors; Ubiquitin; Ventilator Weaning

Muscle wasting negatively affects morbidity and mortality in critically ill patients. This progressive wasting is accompanied by, in general, a normal muscle PS (protein synthesis) rate. In the present study, we investigated whether muscle protein degradation is increased in critically ill patients with sepsis and which proteolytic enzyme systems are involved in this degradation. Eight patients and seven healthy volunteers were studied. In vivo muscle protein kinetics was measured using arteriovenous balance techniques with stable isotope tracers. The activities of the major proteolytic enzyme systems were analysed in combination with mRNA expression of genes related to these proteolytic systems. Results show that critically ill patients with sepsis have a variable but normal muscle PS rate, whereas protein degradation rates are dramatically increased (up to 160%). Of the major proteolytic enzyme systems both the proteasome and the lysosomal systems had higher activities in the patients, whereas calpain and caspase activities were not changed. Gene expression of several genes related to the proteasome system was increased in the patients. mRNA levels of the two main lysosomal enzymes (cathepsin B and L) were not changed but, conversely, genes related to calpain and caspase had a higher expression in the muscles of the patients. In conclusion, the dramatic muscle wasting seen in critically ill patients with sepsis is due to increased protein degradation. This is facilitated by increased activities of both the proteasome and lysosomal proteolytic systems.

Topics: Aged; Calpain; Caspase 3; Cathepsin B; Cathepsin L; Critical Illness; Female; Gene Expression; Humans; Kinetics; Lysosomes; Male; Middle Aged; Muscle Proteins; Muscle, Skeletal; Proteasome Endopeptidase Complex; Protein Biosynthesis; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sepsis