Evidence That Cathepsin B Contributes to Skeletal Muscle Protein Breakdown During Sepsis

Hummel, Robert P.; James, J. Howard; Warner, Brad W.; Hasselgren, Per-Olof; Fischer, Josef E.

doi:10.1001/archsurg.1988.01400260105013

Cited by 24 publications

(15 citation statements)

References 19 publications

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“…These reports are conflicting. Indeed, studies by several groups supported a role for lysosomal (14,15) or Ca 2ϩ -dependent proteinases (8,16). In striking contrast, no evidence for a role of either cathepsins (8) or both lysosomal and Ca 2ϩ -activated proteinases (5) has also been reported.…”

Section: Discussionmentioning

confidence: 99%

“…The most studied proteolytic process in skeletal muscle is the lysosomal pathway. It has been reported that cathepsin B (a major lysosomal proteinase in skeletal muscle with cathepsins L, H, and D) plays an important role in muscle wasting in septic rats (14,15). By contrast, others studies have described no change in cathepsin B or L activities (8) or have reported little if any evidence for increased lysosomal proteolysis (5) in septic muscle.…”

Section: Introductionmentioning

confidence: 99%

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Muscle wasting in a rat model of long-lasting sepsis results from the activation of lysosomal, Ca2+ -activated, and ubiquitin-proteasome proteolytic pathways.

Voisin¹,

Breuillé²,

Combaret³

et al. 1996

J. Clin. Invest.

209

160

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We studied the alterations in skeletal muscle protein breakdown in long lasting sepsis using a rat model that reproduces a sustained and reversible catabolic state, as observed in humans. Rats were injected intravenously with live Escherichia coli ; control rats were pair-fed to the intake of infected rats. Rats were studied in an acute septic phase (day 2 postinfection), in a chronic septic phase (day 6), and in a late septic phase (day 10). The importance of the lysosomal, Ca 2 ϩ -dependent, and ubiquitin-proteasome proteolytic processes was investigated using proteolytic inhibitors in incubated epitrochlearis muscles and by measuring mRNA levels for critical components of these pathways. Protein breakdown was elevated during the acute and chronic septic phases (when significant muscle wasting occurred) and returned to control values in the late septic phase (when wasting was stopped). A nonlysosomal and Ca 2 ϩ -independent process accounted for the enhanced proteolysis, and only mRNA levels for ubiquitin and subunits of the 20 S proteasome, the proteolytic core of the 26 S proteasome that degrades ubiquitin conjugates, paralleled the increased and decreased rates of proteolysis throughout. However, increased mRNA levels for the 14-kD ubiquitin conjugating enzyme E2, involved in substrate ubiquitylation, and for cathepsin B and m-calpain were observed in chronic sepsis. These data clearly support a major role for the ubiquitinproteasome dependent proteolytic process during sepsis but also suggest that the activation of lysosomal and Ca 2 ϩ -dependent proteolysis may be important in the chronic phase. (

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Muscle wasting in a rat model of long-lasting sepsis results from the activation of lysosomal, Ca2+ -activated, and ubiquitin-proteasome proteolytic pathways.

Voisin¹,

Breuillé²,

Combaret³

et al. 1996

J. Clin. Invest.

209

160

View full text Add to dashboard Cite

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“…These studies began three decades ago when Ruff and Secrist (600) first observed that skeletal muscle atrophy caused by experimental sepsis could be prevented by pretreating rats with leupeptin, a cathepsin B inhibitor. Cathepsin B mRNA levels, activity as well as protein degradation rates, were elevated in limb muscles isolated from septic rats (284,329,330,749). The clinical relevance of this finding was reinforced by Helliwell et al (298) who observed greater immunolabeling for cathepsin B in muscle fibers of critically ill patients.…”

Section: Cathepsins In Critical Illnessmentioning

confidence: 92%

“…In critically ill patients, Klaude et al (368) found no changes in the mRNA levels of either cathepsin B or cathepsin L. Interventional studies further challenge the importance of cathepsins. In 1988, Hummel et al (329) reported that leupeptin, a cathepsin B inhibitor, only partially blunted the rise in protein degradation rate caused by experimental sepsis. They concluded that proteases other than cathepsin B might be involved.…”

Section: Cathepsins In Critical Illnessmentioning

confidence: 99%

The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill

Friedrich

Reid

Berghe

et al. 2015

Physiological Reviews

300

329

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Critical illness polyneuropathies (CIP) and myopathies (CIM) are common complications of critical illness. Several weakness syndromes are summarized under the term intensive care unit-acquired weakness (ICUAW). We propose a classification of different ICUAW forms (CIM, CIP, sepsis-induced, steroid-denervation myopathy) and pathophysiological mechanisms from clinical and animal model data. Triggers include sepsis, mechanical ventilation, muscle unloading, steroid treatment, or denervation. Some ICUAW forms require stringent diagnostic features; CIM is marked by membrane hypoexcitability, severe atrophy, preferential myosin loss, ultrastructural alterations, and inadequate autophagy activation while myopathies in pure sepsis do not reproduce marked myosin loss. Reduced membrane excitability results from depolarization and ion channel dysfunction. Mitochondrial dysfunction contributes to energy-dependent processes. Ubiquitin proteasome and calpain activation trigger muscle proteolysis and atrophy while protein synthesis is impaired. Myosin loss is more pronounced than actin loss in CIM. Protein quality control is altered by inadequate autophagy. Ca 2ϩ dysregulation is present through altered Ca 2ϩ homeostasis. We highlight clinical hallmarks, trigger factors, and potential mechanisms from human studies and animal models that allow separation of risk factors that may trigger distinct mechanisms contributing to weakness. During critical illness, altered inflammatory (cytokines) and metabolic pathways deteriorate muscle function. ICUAW prevention/treatment is limited, e.g., tight glycemic control, delaying nutrition, and early mobilization. Future challenges include identification of primary/secondary events during the time course of critical illness, the interplay between membrane excitability, bioenergetic failure and differential proteolysis, and finding new therapeutic targets by help of tailored animal models.

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“…Both complications may overlap in septic patients, yet they present two distinct entities that should not be used synonymously. Whereas ICUAW is most likely accompanied by muscle wasting, muscle wasting is not necessarily associated with ICUAW 2.3 Increased muscle protein degradation during sepsis Data from studies in cultured cells, animals and humans indicate an increase of sepsis-associated muscle protein degradation by several mechanisms, including the ubiquitin proteasome system (UPS) [58][59][60][61] and lysosomal systems [50,[62][63][64]. Calcium-dependent non-lysosomal calpains and pro-apoptotic pathways (caspases) have also been associated with sepsis-induced muscle atrophy [66][67][68].It has been postulated that caspases and calpains are responsible for the cleavage of myofibrillar proteins preceding their proteasomal degradation [65][66][67] and that cleavage is necessary as the proteasome cannot degrade intact myofibrillar proteins.…”

Section: Decreased Muscle Protein Synthesis During Sepsismentioning

confidence: 99%

Intensive care unit—acquired weakness (ICUAW) and muscle wasting in critically ill patients with severe sepsis and septic shock

Schefold

Bierbrauer²,

Weber‐Carstens³

2010

J cachexia sarcopenia muscle

216

174

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Sepsis presents a major health care problem and remains one of the leading causes of death within the intensive care unit (ICU). Therapeutic approaches against severe sepsis and septic shock focus on early identification. Adequate source control, administration of antibiotics, preload optimization by fluid resuscitation and further hemodynamic stabilisation using vasopressors whenever appropriate are considered pivotal within the early—golden—hours of sepsis. However, organ dysfunction develops frequently in and represents a significant comorbidity of sepsis. A considerable amount of patients with sepsis will show signs of severe muscle wasting and/or ICU-acquired weakness (ICUAW), which describes a frequently observed complication in critically ill patients and refers to clinically weak ICU patients in whom there is no plausible aetiology other than critical illness. Some authors consider ICUAW as neuromuscular organ failure, caused by dysfunction of the motor unit, which consists of peripheral nerve, neuromuscular junction and skeletal muscle fibre. Electrophysiologic and/or biopsy studies facilitate further subclassification of ICUAW as critical illness myopathy, critical illness polyneuropathy or critical illness myoneuropathy, their combination. ICUAW may protract weaning from mechanical ventilation and impede rehabilitation measures, resulting in increased morbidity and mortality. This review provides an insight on the available literature on sepsis-mediated muscle wasting, ICUAW and their potential pathomechanisms.

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Evidence That Cathepsin B Contributes to Skeletal Muscle Protein Breakdown During Sepsis

Cited by 24 publications

References 19 publications

Muscle wasting in a rat model of long-lasting sepsis results from the activation of lysosomal, Ca2+ -activated, and ubiquitin-proteasome proteolytic pathways.

Muscle wasting in a rat model of long-lasting sepsis results from the activation of lysosomal, Ca2+ -activated, and ubiquitin-proteasome proteolytic pathways.

The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill

Intensive care unit—acquired weakness (ICUAW) and muscle wasting in critically ill patients with severe sepsis and septic shock

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