PDF(Pubmed)
Abstract：
BACKGROUND: Dysferlin-deficient limb-girdle muscular dystrophy type 2B (Dysf) mice are notorious for their mild phenotype. Raising plasma total cholesterol (CHOL) via apolipoprotein E (ApoE) knockout (KO) drastically exacerbates muscle wasting in Dysf mice. However, dysferlinopathic patients have abnormally reduced plasma high-density lipoprotein cholesterol (HDL-C) levels. The current study aimed to determine whether HDL-C lowering can exacerbate the mild phenotype of dysferlin-null mice.
METHODS: Human cholesteryl ester transfer protein (CETP), a plasma lipid transfer protein not found in mice that reduces HDL-C, and/or its optimal adapter protein human apolipoprotein B (ApoB), were overexpressed in Dysf mice. Mice received a 2% cholesterol diet from 2 months of age and characterized through ambulatory and hanging functional tests, plasma analyses, and muscle histology.
RESULTS: CETP/ApoB expression in Dysf mice caused reduced HDL-C (54.5%) and elevated ratio of CHOL/HDL-C (181.3%) compared to control Dysf mice in plasma, but without raising CHOL. Compared to the severe muscle pathology found in high CHOL Dysf/ApoE double knockout mice, Dysf/CETP/ApoB mice did not show significant changes in ambulation, hanging capacity, increases in damaged area, collagen deposition, or decreases in cross-sectional area and healthy myofibre coverage.
CONCLUSIONS: CETP/ApoB over-expression in Dysf mice decreases HDL-C without increasing CHOL or exacerbating muscle pathology. High CHOL or nonHDL-C caused by ApoE KO, rather than low HDL-C, likely lead to rodent muscular dystrophy phenotype humanization.
METHODS: Human cholesteryl ester transfer protein (CETP), a plasma lipid transfer protein not found in mice that reduces HDL-C, and/or its optimal adapter protein human apolipoprotein B (ApoB), were overexpressed in Dysf mice. Mice received a 2% cholesterol diet from 2 months of age and characterized through ambulatory and hanging functional tests, plasma analyses, and muscle histology.
RESULTS: CETP/ApoB expression in Dysf mice caused reduced HDL-C (54.5%) and elevated ratio of CHOL/HDL-C (181.3%) compared to control Dysf mice in plasma, but without raising CHOL. Compared to the severe muscle pathology found in high CHOL Dysf/ApoE double knockout mice, Dysf/CETP/ApoB mice did not show significant changes in ambulation, hanging capacity, increases in damaged area, collagen deposition, or decreases in cross-sectional area and healthy myofibre coverage.
CONCLUSIONS: CETP/ApoB over-expression in Dysf mice decreases HDL-C without increasing CHOL or exacerbating muscle pathology. High CHOL or nonHDL-C caused by ApoE KO, rather than low HDL-C, likely lead to rodent muscular dystrophy phenotype humanization.
摘要：
背景：Dysferlin缺陷型肢带肌营养不良2B型（Dysf）小鼠因其轻度表型而臭名昭著。通过载脂蛋白E（ApoE）敲除（KO）升高血浆总胆固醇（CHOL）会急剧加剧Dysf小鼠的肌肉萎缩。然而,病态异常患者的血浆高密度脂蛋白胆固醇（HDL-C）水平异常降低。当前的研究旨在确定降低HDL-C是否会加剧dhyperlin-null小鼠的轻度表型。
方法：人胆固醇酯转移蛋白（CETP），一种在小鼠中没有发现的降低HDL-C的血浆脂质转移蛋白，和/或其最佳衔接蛋白人载脂蛋白B（ApoB），在Dysf小鼠中过表达。小鼠从2个月大开始接受2％胆固醇饮食，并通过走动和悬挂功能测试进行表征，血浆分析，和肌肉组织学。
结果：与对照Dysf小鼠相比，Dysf小鼠的CETP/ApoB表达导致血浆中HDL-C降低（54.5％）和CHOL/HDL-C比例升高（181.3％），但没有提高CHOL。与在高CHOLDysf/ApoE双敲除小鼠中发现的严重肌肉病理相比，Dysf/CETP/ApoB小鼠在行走中没有表现出显著的变化，悬挂能力,受损面积增加，胶原蛋白沉积，或减少横截面积和健康的肌纤维覆盖率。
结论：Dysf小鼠中CETP/ApoB过表达降低HDL-C而不增加CHOL或加重肌肉病理。ApoEKO引起的高CHOL或非HDL-C，而不是低HDL-C，可能导致啮齿动物肌营养不良表型人源化。
方法：人胆固醇酯转移蛋白（CETP），一种在小鼠中没有发现的降低HDL-C的血浆脂质转移蛋白，和/或其最佳衔接蛋白人载脂蛋白B（ApoB），在Dysf小鼠中过表达。小鼠从2个月大开始接受2％胆固醇饮食，并通过走动和悬挂功能测试进行表征，血浆分析，和肌肉组织学。
结果：与对照Dysf小鼠相比，Dysf小鼠的CETP/ApoB表达导致血浆中HDL-C降低（54.5％）和CHOL/HDL-C比例升高（181.3％），但没有提高CHOL。与在高CHOLDysf/ApoE双敲除小鼠中发现的严重肌肉病理相比，Dysf/CETP/ApoB小鼠在行走中没有表现出显著的变化，悬挂能力,受损面积增加，胶原蛋白沉积，或减少横截面积和健康的肌纤维覆盖率。
结论：Dysf小鼠中CETP/ApoB过表达降低HDL-C而不增加CHOL或加重肌肉病理。ApoEKO引起的高CHOL或非HDL-C，而不是低HDL-C，可能导致啮齿动物肌营养不良表型人源化。
