Energy-ubiquitin-dependent muscle proteolysis during sepsis in rats is regulated by glucocorticoids.

Tiao, Greg; Fagan, Julie M.; Roegner, Vivien; Lieberman, Melvyn; Wang, Jingjing; Fischer, Josef E.; Hasselgren, Per Olof

doi:10.1172/jci118421

Cited by 224 publications

(228 citation statements)

References 35 publications

Supporting

Mentioning

198

Contrasting

Unclassified

Order By: Relevance

“…In many other conditions with increased muscle proteolysis (e.g. sepsis, trauma, cancer, acidosis, denervation atrophy), it is the ubiquitinproteasome pathway rather than lysosomal proteolysis that is increased (Attaix et al, 1994;Llovera et al, 1995;Medina et al, 1995;Bailey et al, 1996;Tiao et al, 1996). It is likely that amino acids primarily inhibit lysosomal proteolysis in muscle (Wing & Goldberg, 1993).…”

Section: Control By Amino Acids and Hormonesmentioning

confidence: 99%

Untitled

Blommaart

1997

The Histochemical Journal

204

View full text Add to dashboard Cite

SummaryThe rate of proteolysis is an important determinant of the intracellular protein content. Part of the degradation of intracellular proteins occurs in the lysosomes and is mediated by macroautophagy. In liver, macroautophagy is very active and almost completely accounts for starvation-induced proteolysis. Factors inhibiting this process include amino acids, cell swelling and insulin. In the mechanisms controlling macroautophagy, protein phosphorylation plays an important role. Activation of a signal transduction pathway, ultimately leading to phosphorylation of ribosomal protein S6, accompanies inhibition of macroautophagy. Components of this pathway may include a heterotrimeric G i3 -protein, phosphatidylinositol 3-kinase and p70S6 kinase. Recent evidence indicates that lysosomal protein degradation can be selective and occurs via ubiquitin-dependent and -independent pathways.

show abstract

Section: Control By Amino Acids and Hormonesmentioning

confidence: 99%

Untitled

Blommaart

1997

The Histochemical Journal

204

View full text Add to dashboard Cite

show abstract

“…Furthermore, Hasselgren and Fischer [12] showed that dexamethasone (DEX) stimulates proteasome-and calcium-dependent proteolysis in the same cells [13]. Other studies [12,14] confirmed that sepsis induces proteolysis by activation of the ubiquitin-proteasome system, and that this activation was regulated by GCs [15]. These findings represent a unique situation where the increased GC levels described with sepsis are associated with upregulated GR levels in muscle cells, in contrast to most cells, where increased GCs levels are associated with GR downregulation.…”

Section: Introductionmentioning

confidence: 97%

TNF-α and glucocorticoid receptor interaction in L6 muscle cells: A cooperative downregulation of myosin heavy chain

2007

View full text Add to dashboard Cite

Sepsis is associated with increased expression of TNF-α with subsequent activation of nuclear factorkappa B (NF-κB). The glucocorticoid receptor (GR) and NF-κB function as mutual antagonists and induction of the latter is believed to play a major role in the acquired glucocorticoid resistance that occurs in some septic patients. GR expression and function has been reported to be elevated in septic muscle suggesting a limited effect of the activated NF-κB on GR function in this context. In this study, the L6 myocyte cell line was used as an in vitro model for a sepsis-like condition in skeletal muscle. While short or long term treatment with TNF-α had no effect on GR expression, glucocorticoid-dependent downregulation of GR occurred with a kinetic profile that is accelerated relative to that observed in most cells. This downregulation was not affected by co-treatment or prior priming of L6 cells with TNF-α. The synthetic glucocorticoid, dexamethasone (DEX) blunted TNF-α-stimulated NF-κB activation in L6 cells. However, although effective at activating an NF-κB transcriptional response, TNF-α treatment exerted a minimal effect in myoblasts and no effect in myotubes on GR transcriptional activity. This limited impact of TNF-α on GR activity was not universal as TNF-α and DEX exerted an additive effect on the reduction in myosin heavy chain (MHC) protein expression caused by either agent alone. Thus, the selective perseverance of GR function in the presence of increased levels of glucocorticoids and TNF-α during sepsis or other inflammatory states may exacerbate muscle protein breakdown.

show abstract

“…Glucocorticoids increase protein catabolism by opposing the suppression of the transcription of the proteasome C3 a-subunit by nuclear factor-kB (NF-kB), by antagonising the interaction of NF-kB with an NF-kB response element in the C3 subunit promoter region (Du et al, 2000). Also physiological levels of glucocorticoids are necessary, but not sufficient for the catabolic response in rats with metabolic acidosis (Price et al, 1994), starvation (Wing and Goldberg, 1993) and sepsis (Tiao et al, 1996). However, chronic excessive glucocorticoid production, as occurs in Cushing's syndrome is not associated with an increased mRNA for ubiquitin, the ubiquitin-conjugating enzyme, E2 14k , or proteasome subunits (Ralliere et al, 1997), suggesting that other factors may be involved.…”

mentioning

confidence: 99%

Induction of protein catabolism in myotubes by 15(S)-hydroxyeicosatetraenoic acid through increased expression of the ubiquitin–proteasome pathway

2003

View full text Add to dashboard Cite

The potential role of 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) as an intracellular signal for increased protein catabolism and induction of the expression of key components of the ubiquitin -proteasome proteolytic pathway induced by a tumour cachectic factor, proteolysis-inducing factor has been studied in murine C 2 C 12 myotubes. 15(S)-HETE induced protein degradation in these cells with a maximal effect at concentrations between 78 and 312 nM. The effect was attenuated by the polyunsaturated fatty acid, eicosapentaenoic acid (EPA). There was an increase in 'chymotrypsin-like' enzyme activity, the predominant proteolytic activity of the proteasome, in the same concentration range as that inducing total protein degradation, and this effect was also attenuated by EPA. 15(S)-hydroxyeicosatetraenoic acid also increased maximal expression of mRNA for proteasome subunits C2 and C5, as well as the ubiquitin-conjugating enzyme, E2 14k , after 4 h incubation, as determined by quantitative competitive RT -PCR. The concentrations of 15-HETE affecting gene expression were the same as those inducing protein degradation. Western blotting of cellular supernatants of myotubes treated with 15(S)-HETE for 24 h showed increased expression of p42, an ATPase subunit of the regulatory complex at similar concentrations, as well as a decrease in expression of myosin in the same concentration range. 15(S)-hydroxyeicosatetraenoic acid activated binding of nuclear factor-kB (NF-kB) in the myotube nucleus and stimulated degradation of I-kBa. The effect on the NF-kB/I-kBa system was attenuated by EPA. In addition, the NF-kB inhibitor peptide SN50 attenuated the increased chymotrypsinlike enzyme activity in the presence of 15(S)-HETE. These results suggest that 15(S)-HETE induces degradation of myofibrillar proteins in differentiated myotubes through an induction of an increased expression of the regulatory components of the ubiquitinproteasome proteolytic pathway possibly through the intervention of the nuclear transcription factor NF-kB, and that this process is inhibited by EPA.

show abstract

Energy-ubiquitin-dependent muscle proteolysis during sepsis in rats is regulated by glucocorticoids.

Cited by 224 publications

References 35 publications

Untitled

Untitled

TNF-α and glucocorticoid receptor interaction in L6 muscle cells: A cooperative downregulation of myosin heavy chain

Induction of protein catabolism in myotubes by 15(S)-hydroxyeicosatetraenoic acid through increased expression of the ubiquitin–proteasome pathway

Contact Info

Product

Resources

About