MECHANISM OF SKELETAL MUSCLE PROTEOLYTIC METABOLISM IN MAJOR BURN WITH SEPSIS AND ITS SIGNIFICANCE
- VernacularTitle:严重烧伤脓毒症骨骼肌蛋白分解代谢的机制及意义
- Author:
Jiake CHAI
;
Zhiyong SHENG
;
- Publication Type:Journal Article
- Keywords:
burns;
sepsis;
muscle, skeletal;
ubiquitin proteasome;
proteolysis
- From:
Medical Journal of Chinese People's Liberation Army
2001;0(11):-
- CountryChina
- Language:Chinese
-
Abstract:
It is well known that in patients with severe burn, especially when complicated by sepsis, the breakdown of body proteins is acceleraled, producing a hypercalabolic response. Negative nitrogen balance and malnutrition will develop rapidly, predisposing to various complications. High calori intake and enhancement of anabolic process might fail to improve the patient′s nutritional condition. A skeletal muscles account for over 50% of body cell dry weight, their catabolism exerts profound effect on whole body metabolism. By using modern molecular biology techniques, one of the mechanisms underlying skeletal muscle proteolysis is shown to be activation of the ubiquitin proteasome pathway. The role of its possible modulating factors in inducing muscle protein breakdown after burn injury was explored in rat models of burn injury with or without sepsis. Muscle spesimens obtained from severely burned patient with sepsis was also collected for study.The results were as follows. (1)The total and myofibrillar proteolytic rate in extensor digitorum longus (EDL) muscle was increased markedly, especially the expressions of ubiquitin, and mRNA of subunit RC2(the largest subunit of 20s proteasome) were prominantly increased in EDL muscle. There was a significant positive correlation between the proteolytic rate and the expression of mRNA of ubiquitin, or mRNA of subunit RC2, after the stimulation of burn injury. On the other hand, there was no significant change in proteolytic rate and transcription of ubiquitin in soleus (SOL) muscle. (2)The myofibrillar proteolytic rate and the ubiquitin proteasome component were significantly enhanced in rats with sepsis compared with control group. There were significant positive correlations among plasma concentration of endotoxin, TNF ?, cortisol and respective values of myofibrillar proteolytic rate, and ubiquitin proteasome component. (3)There were significant positive correlations between the urinary output of 3 methylhistidine (3 MH)in 24h urine and respective values of plasma concentration of cortisol, TNF ?, and endotoxin in severely burned patients with sepsis. The expressions of ubiquitin mRNA 2 4 kilobase pair (?B), 1.2kb, C 2 subunit mRNA and the protein expressions of ubiquitin in quadriceps femoris muscle were significantly increased compared with the control group. (4)Muscle proteolytic rate was markedly enhanced when myotube was cultured with TNF ?. However, by using the ubiquitin proteasome inhibitor mG132, significant decrease in the muscle proteolyitc rate was observed. (5)Glucocorticoid could increase the skeletal muscle proteolytic rate, especially the myofibrillar proteolytic rate, through activating the ubiquitin proteasome system at gene level. However, this effect could be greatly bluned by glucocorticoid receptor antagonist RU38486. (6)NF ?B activity in skeletal muscle of burned rat with sepsis was markedly increased. However, by using inhibitor of NF ?B, the NF ?B activity was down regwlated in the muscle, and a decrease in the total and myofibrillar proteolytic rate was observed. (7)Decrease in transcriptional expression of ubiquitin and reduction in the skeletal muscle proteolytic rate were found when escharectomy was performed during early stage of burn injury. The results suggested that the treatment strategies for prevention of skeletal muscle proteolysis of postburn sepsis should firstly be aimed at eradication of devitalized tissues, i.e. prevention of sepsis by reonoval of the primary injury. Secondly, attention should be paid to modulating or controlling the process of ubiquitin proteasome pathway in response to burn injury, and this might provide an effective way to reduce skeletal muscle protein wasting by specifically inhibiting the specific enzymes or subunits involved in the enhancement of the activity of ubiquitin proteasome pathway after burn injury. However, more studies in the ubiquitin proteasome proteolytic pathway in severe burn injury are necessary to confirm this assertion.
