Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH, USA.
J Hepatol. 2011 May;54(5):915-21. doi: 10.1016/j.jhep.2010.08.032. Epub 2010 Oct 25.
BACKGROUND & AIMS: The distinct role of portosystemic shunting (PSS) in the pathogenesis of sarcopenia (skeletal muscle loss) that occurs commonly in cirrhosis is unclear. We have previously shown increased expression of myostatin (inhibitor of skeletal muscle mass) in the portacaval anastamosis (PCA) rat model of sarcopenia of PSS. The present study was performed to examine the mechanisms of sarcopenia following PCA.
In PCA and sham operated pair fed control rats, the phenylalanine flooding dose method was used to quantify the fractional and absolute protein synthesis rates in the skeletal muscle over time and in response to follistatin, a myostatin antagonist. The expression of myostatin and markers of satellite cell (myocyte precursors) proliferation and differentiation were quantified by real-time PCR and Western blot analyses.
The absolute synthesis rate (ASR) was lower at 2, 4, and 6 weeks (p<0.05) and the fractional synthesis rate (FSR) of skeletal muscle protein was significantly lower (p<0.05) at week 2 in the PCA rats compared to control rats. Expression of myostatin was elevated while markers of satellite cell proliferation and differentiation were lower at 4 and 6 weeks after PCA. Follistatin increased skeletal muscle mass, muscle FSR and ASR, decreased expression of myostatin protein, and increased expression of markers of satellite cell function.
Sarcopenia associated with PSS is caused by impaired protein synthesis and reduced satellite cell function due to increased myostatin expression. Confirming these alterations in human patients with cirrhosis will provide novel therapeutic targets for sarcopenia of liver disease.
在肝硬化中常见的骨骼肌减少症（骨骼肌损失）的发病机制中，门体分流（PSS）的独特作用尚不清楚。我们之前已经在 PSS 的门腔静脉吻合术（PCA）大鼠骨骼肌减少症模型中显示出肌肉生长抑制素（骨骼肌质量抑制剂）表达增加。本研究旨在研究 PCA 后骨骼肌减少症的发病机制。
在 PCA 和假手术配对喂养对照大鼠中，使用苯丙氨酸洪水剂量法随时间推移和响应于肌肉生长抑制素拮抗剂 follistatin 来定量骨骼肌中的蛋白合成率。通过实时 PCR 和 Western blot 分析来定量肌肉生长抑制素和卫星细胞（肌细胞前体）增殖和分化的标志物的表达。
与对照组大鼠相比，PCA 大鼠在第 2、4 和 6 周（p<0.05）时绝对合成率（ASR）较低，第 2 周时骨骼肌蛋白的分数合成率（FSR）明显较低（p<0.05）。PCA 后 4 周和 6 周时，肌肉生长抑制素表达升高，而卫星细胞增殖和分化的标志物表达降低。Follistatin 增加了骨骼肌质量、肌肉 FSR 和 ASR，降低了肌肉生长抑制素蛋白的表达，并增加了卫星细胞功能的标志物表达。
与 PSS 相关的骨骼肌减少症是由于肌肉生长抑制素表达增加导致蛋白质合成受损和卫星细胞功能降低引起的。在肝硬化患者中证实这些改变将为肝病性骨骼肌减少症提供新的治疗靶点。
