Effect of sepsis on calcium uptake and content in skeletal muscle and regulation in vitro by calcium of total and myofibrillar protein breakdown in control and septic muscle

Benson, D. W.; Bingham, Hal G.

doi:10.1097/00006534-199009000-00107

Cited by 14 publications

(24 citation statements)

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Section: Discussionsupporting

confidence: 92%

“…This finding supports a previous report from our laboratory in which the Ca2+ channel blocker verapamil reduced total protein breakdown in control muscle incubated in the presence of 2.5 mM Ca2' but did not influence total or myofibrillar protein degradation in septic muscle (50). Although uptake of Ca2' and Ca2+ content were increased in muscle from septic rats in that study (50), the increase in Ca2+ content was more pronounced in soleus than in EDL muscle, in contrast to protein breakdown, which was more stimulated in EDL than in soleus (1). Furthermore, Ca2+ in the medium stimulated total, but not myofibrillar, protein degradation in incubated muscle (50), which differs from the pronounced ef- suggest, however, that this system is also involved in the breakdown of myofibrillar proteins in skeletal muscle during certain catabolic conditions, such as denervation, starvation, metabolic acidosis, and cancer (16)(17)(18)(19)(20).…”

Section: Discussionsupporting

confidence: 92%

See 1 more Smart Citation

Sepsis stimulates nonlysosomal, energy-dependent proteolysis and increases ubiquitin mRNA levels in rat skeletal muscle.

Tiao¹,

Fagan²,

Samuels³

et al. 1994

J. Clin. Invest.

239

219

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We tested the role of different intracellular proteolytic pathways in sepsis-induced muscle proteolysis. Sepsis was induced in rats by cecal ligation and puncture; controls were sham operated. Total and myofibrillar proteolysis was determined in incubated extensor digitorum longus muscles as release of tyrosine and 3-methylhistidine, respectively. Lysosomal proteolysis was assessed by using the lysosomotropic agents NH4Cl, chloroquine, leupeptin, and methylamine. Ca2"-dependent proteolysis was determined in the absence or presence of Ca2" or by blocking the Ca2+-dependent proteases calpain I and II. Energy-dependent proteolysis was determined in muscles depleted of ATP by 2-deoxyglucose and 2.4-dinitrophenol. Muscle ubiquitin mRNA and the concentrations of free and conjugated ubiquitin were determined by Northern and Western blots, respectively, to assess the role of the ATP-ubiquitin-dependent proteolytic pathway. Total and myofibrillar protein breakdown was increased during sepsis by 50 and 440%, respectively. Lysosomal and Ca2"-dependent proteolysis was similar in control and septic rats. In contrast, energy-dependent total and myofibrillar protein breakdown was increased by 172% and more than fourfold, respectively, in septic muscle. Ubiquitin mRNA was increased severalfold in septic muscle. The results suggest that the increase in muscle proteolysis during sepsis is due to an increase in nonlysosomal energy-dependent protein breakdown, which may involve the ubiquitin system. (J. Clin. Invest. 1994. 94:2255-2264

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 92%

Sepsis stimulates nonlysosomal, energy-dependent proteolysis and increases ubiquitin mRNA levels in rat skeletal muscle.

Tiao¹,

Fagan²,

Samuels³

et al. 1994

J. Clin. Invest.

239

219

View full text Add to dashboard Cite

show abstract

“…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%

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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“…Increased calpain-dependent protein degradation in sepsis is well established [85]. Calpains are thought to be activated predominantly by intracellular calcium, which can be increased in sepsis (see later in this review and [86]). Activation of calpains also reduces Akt phosphorylation and may therefore contribute to decreased protein synthesis [87].…”

Section: Neuropathy and Nerve Activitymentioning

confidence: 94%

“…In skeletal muscle, the sarcoplasmic reticulum contributes to calcium homeostasis and is the organelle responsible in muscle for calcium binding and release. Sepsis has marked effects on calcium homeostasis, increasing intracellular calcium in limb skeletal muscle [86], reducing calcium binding in isolated sarcoplasmic reticular membrane [90], decreasing release of calcium from the sarcoplasmic reticulum and increasing the sensitivity of contractile proteins to calcium [91]. Several of these activities (e.g.…”

Section: Altered Function Of the Sarcoplasmic Reticulummentioning

confidence: 99%

Molecular mechanisms of intensive care unit-acquired weakness

Bloch¹,

Polkey²,

Griffiths³

et al. 2011

Eur Respir J

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Intensive care unit-acquired weakness (ICUAW) is an increasingly recognised and important clinical consequence of critical illness. It is associated with significant morbidity and mortality. The aetiology of this disease is not well understood. The purpose of this article is to review our understanding of the molecular pathogenesis of ICUAW in the context of current knowledge of clinical risk factors and aetiology.Key features of the disease are loss of muscle mass resulting from a shift in the dynamic balance of muscle protein synthesis and breakdown and a reduction in force-generating capacity. These alternations are secondary to neuropathy, disruption of the myofilament structure and function, a disrupted sarcoplasmic reticulum, electrical inexcitability and bioenergenetic failure.As knowledge and understanding of ICUAW grows, potential therapeutic targets will be identified, hopefully leading to multiple strategies for prevention and treatment of this important condition.

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Effect of sepsis on calcium uptake and content in skeletal muscle and regulation in vitro by calcium of total and myofibrillar protein breakdown in control and septic muscle

Cited by 14 publications

References 0 publications

Sepsis stimulates nonlysosomal, energy-dependent proteolysis and increases ubiquitin mRNA levels in rat skeletal muscle.

Sepsis stimulates nonlysosomal, energy-dependent proteolysis and increases ubiquitin mRNA levels in rat skeletal muscle.

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

Molecular mechanisms of intensive care unit-acquired weakness

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