Proteasome blockers inhibit protein breakdown in skeletal muscle after burn injury in rats

1998 ◽  
Vol 95 (2) ◽  
pp. 225-233 ◽  
Author(s):  
Cheng-Hui FANG ◽  
Jing Jing WANG ◽  
Scott HOBLER ◽  
Bing Guo LI ◽  
Josef E. FISCHER ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Burn Injury ◽  
Muscle Protein ◽  
Total Body Surface Area ◽  
26S Proteasome ◽  
20S Proteasome ◽  
Mrna Levels ◽  
Protein Breakdown ◽  
Turnover Rates ◽  
Muscle Protein Breakdown

1.Burn injury stimulates ubiquitin-dependent protein breakdown in skeletal muscle. The 20S proteasome is the proteolytic core of the 26S proteasome that degrades ubiquitin conjugates. We examined the effects of the proteasome inhibitors N-acetyl-l-leucinyl-L-leucinal-l-norleucinal (LLnL), lactacystin and β-lactone on protein breakdown in muscles from burned rats. 2.A full-thickness burn of 30% total body surface area was inflicted on the back of rats. Control rats underwent a sham procedure. After 24 ;h, extensor digitorum longus muscles were incubated in the absence or presence of 20S proteasome blocker and protein turnover rates and ubiquitin mRNA levels were determined. 3.LLnL resulted in a dose- and time-dependent inhibition of total protein breakdown in incubated muscles from burned rats. Lactacystin and β-lactone blocked both total and myofibrillar muscle protein breakdown. In addition to inhibiting protein breakdown, LLnL increased ubiquitin mRNA levels, possibly reflecting inhibited proteasome-associated RNase activity. 4.Inhibited muscle protein breakdown caused by LLnL, lactacystin and β-lactone supports the concept that the ubiquitin–proteasome pathway plays a central role in burn-induced muscle proteolysis. Because the proteasome has multiple important functions in the cell, in addition to regulating general protein breakdown, further studies are needed to test the role of proteasome blockers in the treatment or prevention of muscle catabolism.

scholarly journals Treatment of burned rats with insulin-like growth factor I inhibits the catabolic response in skeletal muscle

1998 ◽  
Vol 275 (4) ◽  
pp. R1091-R1098 ◽  
Author(s):  
Cheng-Hui Fang ◽  
Bing-Guo Li ◽  
Jing Jing Wang ◽  
Josef E. Fischer ◽  
Per-Olof Hasselgren
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Burn Injury ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Protein Breakdown ◽  
Turnover Rates ◽  
Breakdown Rates ◽  
Igf I ◽  
Catabolic Response

Thermal injury is associated with a pronounced catabolic response in skeletal muscle, reflecting inhibited protein synthesis and increased protein breakdown, in particular myofibrillar protein breakdown. Administration of insulin-like growth factor I (IGF-I) has a nitrogen-sparing effect after burn injury, but the influence of this treatment on protein turnover rates in skeletal muscle is not known. In the present study, we examined the effect of IGF-I on muscle protein synthesis and breakdown rates following burn injury in rats. After a 30% total body surface area burn injury or sham procedure, rats were treated with a continuous infusion of IGF-I (3.5 or 7 mg ⋅ kg−1 ⋅ 24 h−1) for 24 h. Protein synthesis and breakdown rates were determined in incubated extensor digitorum longus muscles. Burn injury resulted in increased total and myofibrillar protein breakdown rates and reduced protein synthesis in muscle. The increase in protein breakdown rates was blocked by both doses of IGF-I and the burn-induced inhibition of muscle protein synthesis was partially reversed by the higher dose of the hormone. IGF-I did not influence muscle protein turnover rates in nonburned rats. The results suggest that the catabolic response to burn injury in skeletal muscle can be inhibited by IGF-I.

Ghrelin inhibits skeletal muscle protein breakdown in rats with thermal injury through normalizing elevated expression of E3 ubiquitin ligases MuRF1 and MAFbx

2009 ◽  
Vol 296 (4) ◽  
pp. R893-R901 ◽  
Author(s):  
Ambikaipakan Balasubramaniam ◽  
Rashika Joshi ◽  
Chunhua Su ◽  
Lou Ann Friend ◽  
Sulaiman Sheriff ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Mrna Expression ◽  
Burn Injury ◽  
Muscle Protein ◽  
Ubiquitin Ligases ◽  
Myofibrillar Protein ◽  
E3 Ubiquitin Ligases ◽  
Protein Breakdown ◽  
Skeletal Muscle Protein ◽  
Muscle Protein Breakdown

We previously determined that ghrelin synthesis was downregulated after burn injury and that exogenous ghrelin retained its ability both to stimulate food intake and to restore plasma growth hormone levels in burned rats. These observations and the finding that anabolic hormones can attenuate skeletal muscle catabolism led us to investigate whether ghrelin could attenuate burn-induced skeletal muscle protein breakdown in rats. These studies were performed in young rats (50–60 g) 24 h after ∼30% total body surface area burn injury. Burn injury increased total and myofibrillar protein breakdown in extensor digitorum longus (EDL) muscles assessed by in vitro tyrosine and 3-methyl-histidine release, respectively. Continuous 24-h administration of ghrelin (0.2 mg·kg−1·h−1) significantly inhibited both total and myofibrillar protein breakdown in burned rats. Ghrelin significantly attenuated burn-induced changes in mRNA expression of IGFBP-1 and IGFBP-3 in liver. In EDL, ghrelin attenuated the increases in mRNA expression of the binding proteins, but had no significant effect on reduced expression of IGF-I. Ghrelin markedly reduced the elevated mRNA expression of TNF-α and IL-6 in EDL muscle that occurred after burn. Moreover, ghrelin normalized plasma glucocorticoid levels, which were elevated after burn. Expression of the muscle-specific ubiquitin-ligating enzyme (E3) ubiquitin ligases MuRF1 and MAFbx were markedly elevated in both EDL and gastrocnemius and were normalized by ghrelin. These results suggest that ghrelin is a powerful anticatabolic compound that reduces skeletal muscle protein breakdown through attenuating multiple burn-induced abnormalities.

Sepsis in mice stimulates muscle proteolysis in the absence of IL-6

1998 ◽  
Vol 275 (6) ◽  
pp. R1983-R1991 ◽  
Author(s):  
Arthur Williams ◽  
Jing Jing Wang ◽  
Li Wang ◽  
Xiaoyan Sun ◽  
Josef E. Fischer ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Muscle Protein ◽  
Mrna Levels ◽  
Protein Breakdown ◽  
Wild Type ◽  
Dot Blot ◽  
Muscle Protein Breakdown ◽  
L6 Myotubes ◽  
Identical Response ◽  
Breakdown Rates

We tested the role of interleukin-6 (IL-6) in sepsis-induced muscle proteolysis by determining ubiquitin mRNA levels and protein breakdown rates in incubated extensor digitorum longus muscles from septic and sham-operated IL-6 knockout and wild-type mice. In addition, the effect of treatment of mice with human recombinant IL-6 on muscle protein breakdown rates was determined. Finally, protein breakdown rates were measured in myotubes treated for up to 48 h with different concentrations of IL-6. Sepsis in wild-type mice resulted in an approximately ninefold increase in plasma IL-6 levels, whereas IL-6 was not detectable in plasma of sham-operated or septic IL-6 knockout mice. Total and myofibrillar muscle protein breakdown rates were increased by ∼30% and threefold, respectively, in septic IL-6 wild-type mice with an almost identical response noted in septic IL-6 knockout mice. Ubiquitin mRNA levels determined by dot blot analysis were increased during sepsis in muscles from both IL-6 knockout and wild-type mice, although the increase was less pronounced in IL-6 knockout than in wild-type mice. Treatment of normal mice or of cultured L6 myotubes with IL-6 did not influence protein breakdown rates. The present results suggest that IL-6 does not regulate muscle proteolysis during sepsis.

Tumor necrosis factor induces skeletal muscle protein breakdown in rats

1991 ◽  
Vol 260 (5) ◽  
pp. E727-E730 ◽  
Author(s):  
M. N. Goodman
Keyword(s):  
Skeletal Muscle ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Muscle Protein ◽  
Nitrogen Excretion ◽  
Protein Breakdown ◽  
Skeletal Muscle Protein ◽  
Muscle Protein Breakdown ◽  
Necrosis Factor

The metabolic response to infection includes loss of lean tissue and increased nitrogen excretion. The loss of muscle tissue during infection results in large part from accelerated skeletal muscle protein breakdown. Recent studies suggest that macrophage-derived products secreted during infection may signal increased muscle proteolysis. To test this, in the present report the ability of interleukin (IL-1) and tumor necrosis factor (TNF) to enhance muscle proteolysis was examined. Young rats were injected intravenously with either recombinant human IL-1 or TNF. For comparison some rats were injected with bacterial endotoxin. Eight hours after each treatment, the extensor digitorum longus muscles were isolated and incubated in vitro to assess muscle proteolysis by measuring tyrosine and 3-methyl-L-histidine release by the incubated muscles. Treatment of rats with either IL-1, TNF, or endotoxin all induced fever, increased serum lactate, and reduced serum zinc levels. Despite similar metabolic changes, muscle proteolysis responded differently. As expected, endotoxin treatment enhanced muscle protein breakdown, whereas IL-1 treatment was without effect. On the other hand, TNF was effective in accelerating muscle protein breakdown. TNF addition in vitro failed to enhance muscle proteolysis by incubated muscles, suggesting that its effects may be mediated in an indirect manner; however, a direct mode of action cannot yet be ruled out. Overall, the data indicate that the acute administration of TNF can signal increased muscle proteolysis similar to that observed during infection.

Role of Interleukin-6 in Skeletal Muscle Protein Breakdown and Cathepsin Activity in vivo

1996 ◽  
Vol 28 (5) ◽  
pp. 361-366 ◽  
Author(s):  
J. Fujita ◽  
T. Tsujinaka ◽  
C. Ebisui ◽  
M. Yano ◽  
H. Shiozaki ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Interleukin 6 ◽  
Muscle Protein ◽  
Protein Breakdown ◽  
Skeletal Muscle Protein ◽  
Muscle Protein Breakdown ◽  
Cathepsin Activity
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