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首页> 外文期刊>American Journal of Physiology >Treatment of rats with calpain inhibitors prevents sepsis-induced muscle proteolysis independent of atrogin-1/MAFbx and MuRF1 expression.
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Treatment of rats with calpain inhibitors prevents sepsis-induced muscle proteolysis independent of atrogin-1/MAFbx and MuRF1 expression.

机译：用钙蛋白酶抑制剂治疗大鼠可预防败血症诱导的肌肉蛋白水解，而不受atrogin-1 / MAFbx和MuRF1表达的影响。

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Muscle wasting in sepsis is a significant clinical problem because it results in muscle weakness and fatigue that may delay ambulation and increase the risk for thromboembolic and pulmonary complications. Treatments aimed at preventing or reducing muscle wasting in sepsis, therefore, may have important clinical implications. Recent studies suggest that sepsis-induced muscle proteolysis may be initiated by calpain-dependent release of myofilaments from the sarcomere, followed by ubiquitination and degradation of the myofilaments by the 26S proteasome. In the present experiments, treatment of rats with one of the calpain inhibitors calpeptin or BN82270 inhibited protein breakdown in muscles from rats made septic by cecal ligation and puncture. The inhibition of protein breakdown was not accompanied by reduced expression of the ubiquitin ligases atrogin-1/MAFbx and MuRF1, suggesting that the ubiquitin-proteasome system is regulated independent of the calpain system in septic muscle. When incubated muscleswere treated in vitro with calpain inhibitor, protein breakdown rates and calpain activity were reduced, consistent with a direct effect in skeletal muscle. Additional experiments suggested that the effects of BN82270 on muscle protein breakdown may, in part, reflect inhibited cathepsin L activity, in addition to inhibited calpain activity. When cultured myoblasts were transfected with a plasmid expressing the endogenous calpain inhibitor calpastatin, the increased protein breakdown rates in dexamethasone-treated myoblasts were reduced, supporting a role of calpain activity in atrophying muscle. The present results suggest that treatment with calpain inhibitors may prevent sepsis-induced muscle wasting.
机译：败血症中的肌肉浪费是一个重要的临床问题，因为它会导致肌肉无力和疲劳，这可能会延迟走动并增加血栓栓塞和肺部并发症的风险。因此，旨在预防或减少败血症中肌肉消耗的治疗可能具有重要的临床意义。最近的研究表明，败血症诱导的肌肉蛋白水解可能是由钙蛋白酶依赖的肌纤维从肌小节的释放所致，随后是26S蛋白酶体的泛素化和肌纤维的降解。在本实验中，用一种钙蛋白酶抑制剂calpeptin或BN82270处理大鼠可抑制因盲肠结扎和穿刺而脓毒症的大鼠肌肉中的蛋白质分解。蛋白质降解的抑制并不伴随泛素连接酶atrogin-1 / MAFbx和MuRF1的表达降低，这表明在脓毒症肌肉中，泛素-蛋白酶体系统不受钙蛋白酶系统的调节。当用钙蛋白酶抑制剂体外处理孵育的肌肉时，蛋白质分解速率和钙蛋白酶活性降低，这与骨骼肌的直接作用一致。额外的实验表明，BN82270对肌肉蛋白质分解的影响除了抑制钙蛋白酶活性外，还可能部分反映了组织蛋白酶L活性的抑制。当用表达内源钙蛋白酶抑制剂钙蛋白酶抑制剂的质粒转染培养的成肌细胞时，地塞米松处理的成肌细胞中增加的蛋白质分解率降低，从而支持了钙蛋白酶活性在萎缩性肌肉中的作用。目前的结果表明，用钙蛋白酶抑制剂治疗可以预防败血症引起的肌肉消瘦。

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