Protein Metabolism in Different Types of Skeletal Muscle During Early and Late Sepsis in Rats

Hasselgren, Per Olof; Talamini, Mark A.; James, J. Howard; Fischer, Josef E.

doi:10.1001/archsurg.1986.01400080064011

Cited by 114 publications

(39 citation statements)

References 29 publications

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“…Therefore, it is understandable that AIB uptake by the soleus muscle was significantly less in TB rats with cancer cachexia and in PF rats with severely reduced food intake than in control FF rats, although the AIB uptakes of the muscle in PF and TB rats were not significantly different. The reduced AIB uptake by lean skeletal muscle of these rats was similar to the metabolic disturbance seen in sepsis and following injury [17,18,22,23], that is, inhibition of AIB uptake by skeletal muscle. on the other hand, AIB uptake by the liver was significantly greater in PF and TB rats than in FF rats, and was significantly more in PF rats than in TB rats.…”

Section: Food Intake and Tumor Growthsupporting

confidence: 59%

“…In sepsis or after injury, protein synthesis in muscle is reported to increase [17,29,30], to remain unchanged [23,31], or to decrease [19,32,33], although the characteristic metabolic changes in sepsis and after injury are accelerated muscle proteolysis and increased peripheral release of amino acids, concomitant with stimulated amino acid uptake by the liver [17,18]. Amino acid uptake does not necessarily reflect the rate of protein synthesis, but low amino acid transport into tissues may at least be associated with a low rate of protein synthesis.…”

Section: Food Intake and Tumor Growthmentioning

confidence: 99%

“…A large portion of the amino acids taken up by the liver is used for increased protein synthesis and gluconeogenesis [19][20][21]. Recent studies showed that amino acid uptake by septic skeletal muscle was reduced and that muscle wasting during sepsis was caused by increased protein degradation, not by decreased protein synthesis [22,23].…”

mentioning

confidence: 99%

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Distribution of a non-metabolizable amino acid in different tissues of tumor-bearing rats in cachexia.

Takehara

James

Fischer

1990

J. Clin. Biochem. Nutr.

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Section: Food Intake and Tumor Growthsupporting

confidence: 59%

Section: Food Intake and Tumor Growthmentioning

confidence: 99%

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Distribution of a non-metabolizable amino acid in different tissues of tumor-bearing rats in cachexia.

Takehara

James

Fischer

1990

J. Clin. Biochem. Nutr.

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“…Three models of sepsis are commonly used to investigate the alterations in skeletal muscle protein turnover, i.e., cecal ligation and puncture (4,5), implantation of a sterilized fecalagar pellet containing Escherichia coli and Bacteroides fragilis (6)(7)(8) and endotoxin administration (9,10). None of these reproduces the lasting muscle wasting observed in septic patients.…”

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

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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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“…Many studies have provided evidence that muscle atrophy in sepsis is primarily the result of increased protein breakdown [Hasselgren et al, 1986[Hasselgren et al, , 1989Ash and Griffin, 1989] via the ubiquitinproteasome pathway [Tiao et al, 1994[Tiao et al, , 1997. Indeed, both atrogin-1/MAFbx and MuRF1 are upregulated in the muscle of septic models induced by either cecal ligation and puncture [Wray et al, 2003] or lipopolysaccharide (LPS) administration [Dehoux et al, 2003].…”

mentioning

confidence: 99%

Curcumin prevents lipopolysaccharide‐induced atrogin‐1/MAFbx upregulation and muscle mass loss

Jin

2006

J of Cellular Biochemistry

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Because elevated ubiquitin ligase atrogin-1/MAFbx and MuRF1 mediate skeletal muscle wasting associated with various catabolic conditions, the signaling pathways involved in the upregulation of these genes under pathological conditions are considered therapeutic targets. AKT and NF-κB have been previously shown to regulate the expression of atrogin-1/MAFbx or MuRF1, respectively. In addition, we recently found that p38 MAPK mediates TNF-α upregulation of atrogin-1/MAFbx expression, suggesting that multiple signaling pathways mediate muscle wasting in inflammatory diseases. To date, however, these advances have not resulted in a practical clinical intervention for disease-induced muscle wasting. In the present study, we tested the effect of curcumin-a non-toxic anti-inflammatory reagent that inhibits p38 and NF-κB-on lipopolysaccharide (LPS)-induced muscle wasting in mice. Daily intraperitoneal (i.p.) injection of curcumin (10-60 μg/kg) for 4 days inhibited, in a dose-dependent manner, the LPS-stimulated (1 mg/kg, i.p.) increase of atrogin-1/MAFbx expression in gastrocnemius and extensor digitorum longus (EDL) muscles, resulting in the attenuation of muscle protein loss. It should also be noted that curcumin administration did not alter the basal expression of atrogin-1/MAFbx, nor did it affect LPS-stimulated MuRF1 and polyubiquitin expression. LPS activated p38 and NF-κB, while inhibiting AKT; whereas, curcumin administration inhibited LPS-stimulated p38 activation, without altering the effect of LPS on NF-κB and AKT. These results indicate that curcumin is effective in blocking LPS-induced loss of muscle mass through the inhibition of p38-mediated upregulation of atrogin-1/MAFbx. Keywords endotoxemia; ubiquitin-proteasome pathway; p38; AKT; NF-κB Muscle wasting is a major feature of the cachexia associated with such diseases as sepsis, cancer, AIDS, diabetes, uremia, congestive heart failure, and chronic obstructive pulmonary disease (COPD) [Hasselgren, 1995;Tisdale, 1997]. Muscle wasting increases patient morbidity and mortality through disability, injury, osteoporosis, impairment of respiratory function, and depletion of the free amino acid pool for enzyme and antibody production. The progressive loss of body protein becomes lethal when it depletes approximately 40% of lean body mass [Winick, 1979]. However, to date, no drug has been approved for muscle wasting. Muscle wasting is primarily caused by accelerated muscle protein breakdown via the ubiquitin-proteasome pathway . Proteins degraded by this pathway are first covalently linked to a chain of ubiquitin molecules that marks them for rapid breakdown by the 26S proteasome. The selectivity of ubiquitin targeting is primarily a function of ubiquitin ligase (E3 protein) [Hershko and Ciechanover, 1998]. Two muscleenriched ubiquitin ligases, atrogin-1/MAFbx and MuRF1, are rate limiting for muscle protein loss in various catabolic conditions. Expression of these two ubiquitin ligases is upregulated in the muscle of various animal models of muscle atrophy,...

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Protein Metabolism in Different Types of Skeletal Muscle During Early and Late Sepsis in Rats

Cited by 114 publications

References 29 publications

Distribution of a non-metabolizable amino acid in different tissues of tumor-bearing rats in cachexia.

Distribution of a non-metabolizable amino acid in different tissues of tumor-bearing rats in cachexia.

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

Curcumin prevents lipopolysaccharide‐induced atrogin‐1/MAFbx upregulation and muscle mass loss

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