Protein metabolism and gene expression in skeletal muscle of critically ill patients with sepsis.

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.

[1]  F. Maltais,et al.  Mechanical ventilation-induced diaphragm disuse in humans triggers autophagy. , 2010, American journal of respiratory and critical care medicine.

[2]  Luca Scorrano,et al.  Mitochondrial fission and remodelling contributes to muscle atrophy , 2010, The EMBO journal.

[3]  A. Mebazaa,et al.  Activation of the ubiquitin proteolytic pathway in human septic heart and diaphragm. , 2010, Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology.

[4]  M. Rennie,et al.  Facts, noise and wishful thinking: muscle protein turnover in aging and human disuse atrophy , 2010, Scandinavian journal of medicine & science in sports.

[5]  Ivan Dikic,et al.  Nix is a selective autophagy receptor for mitochondrial clearance , 2010, EMBO reports.

[6]  G. Supinski,et al.  Caspase and calpain activation both contribute to sepsis-induced diaphragmatic weakness. , 2009, Journal of applied physiology.

[7]  P. Greenhaff,et al.  The involvement of the ubiquitin proteasome system in human skeletal muscle remodelling and atrophy. , 2008, Biochimica et biophysica acta.

[8]  J. Timmons,et al.  Dysregulation of Mitochondrial Dynamics and the Muscle Transcriptome in ICU Patients Suffering from Sepsis Induced Multiple Organ Failure , 2008, PloS one.

[9]  A. Goldberg,et al.  FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells. , 2007, Cell metabolism.

[10]  A. Goldberg,et al.  FoxO3 controls autophagy in skeletal muscle in vivo. , 2007, Cell metabolism.

[11]  A. Russell,et al.  Muscle atrophy and hypertrophy signaling in patients with chronic obstructive pulmonary disease. , 2007, American journal of respiratory and critical care medicine.

[12]  S. Powers,et al.  Oxidative stress and disuse muscle atrophy. , 2007, Journal of applied physiology.

[13]  B. Ahlman,et al.  Proteasome proteolytic activity in skeletal muscle is increased in patients with sepsis. , 2007, Clinical science.

[14]  O. Ljungqvist,et al.  Derangements in mitochondrial metabolism in intercostal and leg muscle of critically ill patients with sepsis-induced multiple organ failure. , 2006, American journal of physiology. Endocrinology and metabolism.

[15]  Bingwen Jin,et al.  Activation of the ubiquitin-proteasome pathway in the diaphragm in chronic obstructive pulmonary disease. , 2006, American journal of respiratory and critical care medicine.

[16]  G. Supinski,et al.  Caspase activation contributes to endotoxin-induced diaphragm weakness. , 2006, Journal of applied physiology.

[17]  D. Taillandier,et al.  Lysosomal proteolysis in skeletal muscle. , 2005, The international journal of biochemistry & cell biology.

[18]  F. Hammarqvist,et al.  An assay of microsomal membrane-associated proteasomes demonstrates increased proteolytic activity in skeletal muscle of intensive care unit patients. , 2005, Clinical nutrition.

[19]  Wei Wei,et al.  Sepsis stimulates calpain activity in skeletal muscle by decreasing calpastatin activity but does not activate caspase-3. , 2005, American journal of physiology. Regulatory, integrative and comparative physiology.

[20]  J. Wernerman,et al.  Amino acid metabolism in leg muscle after an endotoxin injection in healthy volunteers. , 2005, American journal of physiology. Endocrinology and metabolism.

[21]  J. Wernerman,et al.  Contractile protein breakdown in human leg skeletal muscle as estimated by [2H3]-3-methylhistidine: a new method. , 2004, Metabolism: clinical and experimental.

[22]  E. Hoffman,et al.  Constitutive activation of MAPK cascade in acute quadriplegic myopathy , 2004, Annals of neurology.

[23]  J. Wernerman,et al.  Effects on skeletal muscle of intravenous glutamine supplementation to ICU patients , 2004, Intensive Care Medicine.

[24]  P. Hasselgren,et al.  Sepsis upregulates the gene expression of multiple ubiquitin ligases in skeletal muscle. , 2003, The international journal of biochemistry & cell biology.

[25]  I. Richard,et al.  Down-regulation of genes in the lysosomal and ubiquitin-proteasome proteolytic pathways in calpain-3-deficient muscle. , 2003, The international journal of biochemistry & cell biology.

[26]  H. Barle,et al.  Longitudinal pattern of glutamine/glutamate balance across the leg in long-stay intensive care unit patients. , 2002, Clinical nutrition.

[27]  G. Biolo,et al.  Regulation of muscle cathepsin B proteolytic activity in protein-depleted patients with chronic diseases. , 2002, Clinical nutrition.

[28]  G. Gibson,et al.  Skeletal muscle mRNA levels for cathepsin B, but not components of the ubiquitin-proteasome pathway, are increased in patients with lung cancer referred for thoracotomy. , 2002, Clinical science.

[29]  D. Attaix,et al.  Identification of cathepsin L as a differentially expressed message associated with skeletal muscle wasting. , 2001, The Biochemical journal.

[30]  C. Pickart,et al.  Mechanisms underlying ubiquitination. , 2001, Annual review of biochemistry.

[31]  A. Goldberg,et al.  What do we really know about the ubiquitin-proteasome pathway in muscle atrophy? , 2001, Current opinion in clinical nutrition and metabolic care.

[32]  T. Pritts,et al.  Dantrolene reduces serum TNFalpha and corticosterone levels and muscle calcium, calpain gene expression, and protein breakdown in septic rats. , 2001, Shock.

[33]  P. Essén,et al.  Protein-sparing effect in skeletal muscle of growth hormone treatment in critically ill patients. , 2000, Annals of surgery.

[34]  T. Pritts,et al.  The gene expression of ubiquitin ligase E3alpha is upregulated in skeletal muscle during sepsis in rats-potential role of glucocorticoids. , 2000, Biochemical and biophysical research communications.

[35]  J. Wang,et al.  Activity and expression of the 20S proteasome are increased in skeletal muscle during sepsis. , 1999, The American journal of physiology.

[36]  W. Baumeister,et al.  The 26S proteasome: a molecular machine designed for controlled proteolysis. , 1999, Annual review of biochemistry.

[37]  J. Fischer,et al.  Sepsis is associated with increased ubiquitinconjugating enzyme E214k mRNA in skeletal muscle. , 1999, American journal of physiology. Regulatory, integrative and comparative physiology.

[38]  S. Loening,et al.  Cathepsins B, H, L and cysteine protease inhibitors in malignant prostate cell lines, primary cultured prostatic cells and prostatic tissue. , 1999, European journal of cancer.

[39]  D. Béchet,et al.  Glucose controls cathepsin expression in Ras-transformed fibroblasts. , 1998, Archives of biochemistry and biophysics.

[40]  Griffiths,et al.  Muscle fibre atrophy in critically ill patients is associated with the loss of myosin filaments and the presence of lysosomal enzymes and ubiquitin , 1998, Neuropathology and applied neurobiology.

[41]  K. Nair,et al.  Effects of aging on in vivo synthesis of skeletal muscle myosin heavy-chain and sarcoplasmic protein in humans. , 1997, American journal of physiology. Endocrinology and metabolism.

[42]  K. Andersson,et al.  Longitudinal changes of biochemical parameters in muscle during critical illness. , 1997, Metabolism: clinical and experimental.

[43]  A. Engel,et al.  Acute quadriplegic myopathy: Analysis of myosin isoforms and evidence for calpain‐mediated proteolysis , 1997, Muscle & nerve.

[44]  G. Tiao,et al.  Intracellular regulation of protein degradation during sepsis is different in fast- and slow-twitch muscle. , 1997, The American journal of physiology.

[45]  T. Meyer,et al.  Sepsis is associated with increased mRNAs of the ubiquitin-proteasome proteolytic pathway in human skeletal muscle. , 1997, The Journal of clinical investigation.

[46]  B. Beaufrère,et al.  Increased mRNA levels for components of the lysosomal, Ca2+-activated, and ATP-ubiquitin-dependent proteolytic pathways in skeletal muscle from head trauma patients. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[47]  M. Monden,et al.  Muscle undergoes atrophy in association with increase of lysosomal cathepsin activity in interleukin-6 transgenic mouse. , 1995, Biochemical and biophysical research communications.

[48]  G. Biolo,et al.  Transmembrane transport and intracellular kinetics of amino acids in human skeletal muscle. , 1995, The American journal of physiology.

[49]  G. Tiao,et al.  Sepsis stimulates nonlysosomal, energy-dependent proteolysis and increases ubiquitin mRNA levels in rat skeletal muscle. , 1994, The Journal of clinical investigation.

[50]  B. Warner,et al.  Evidence that cathepsin B contributes to skeletal muscle protein breakdown during sepsis. , 1988, Archives of surgery.

[51]  R. Ruff,et al.  Inhibitors of prostaglandin synthesis or cathepsin B prevent muscle wasting due to sepsis in the rat. , 1984, The Journal of clinical investigation.