Limb-girdle muscular dystrophy type 2B causes HDL-C abnormalities in patients and statin-resistant muscle wasting in dysferlin-deficient mice.

IF 5.3 2区 医学 Q2 CELL BIOLOGY Skeletal Muscle Pub Date : 2022-11-29 DOI:10.1186/s13395-022-00308-6
Zoe White, Zeren Sun, Elodie Sauge, Dan Cox, Graham Donen, Dmitri Pechkovsky, Volker Straub, Gordon A Francis, Pascal Bernatchez
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引用次数: 3

Abstract

Limb-girdle muscular dystrophy (MD) type 2B (LGMD2B) and Duchenne MD (DMD) are caused by mutations to the Dysferlin and Dystrophin genes, respectively. We have recently demonstrated in typically mild dysferlin- and dystrophin-deficient mouse models that increased plasma cholesterol levels severely exacerbate muscle wasting, and that DMD patients display primary dyslipidemia characterized by elevated plasma cholesterol and triglycerides. Herein, we investigate lipoprotein abnormalities in LGMD2B and if statin therapy protects dysferlin-deficient mice (Dysf) from muscle damage. Herein, lipoproteins and liver enzymes from LGMD2B patients and dysferlin-null (Dysf) mice were analyzed. Simvastatin, which exhibits anti-muscle wasting effects in mouse models of DMD and corrects aberrant expression of key markers of lipid metabolism and endogenous cholesterol synthesis, was tested in Dysf mice. Muscle damage and fibrosis were assessed by immunohistochemistry and cholesterol signalling pathways via Western blot. LGMD2B patients show reduced serum high-density lipoprotein cholesterol (HDL-C) levels compared to healthy controls and exhibit a greater prevalence of abnormal total cholesterol (CHOL)/HDL-C ratios despite an absence of liver dysfunction. While Dysf mice presented with reduced CHOL and associated HDL-C and LDL-C-associated fractions, simvastatin treatment did not prevent muscle wasting in quadriceps and triceps muscle groups or correct aberrant low-density lipoprotein receptor (LDLR) and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) protein expression. LGMD2B patients present with reduced serum concentrations of HDL-C, a major metabolic comorbidity, and as a result, statin therapy is unlikely to prevent muscle wasting in this population. We propose that like DMD, LGMD2B should be considered as a new type of genetic dyslipidemia.

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2B型肢带性肌营养不良症导致患者HDL-C异常,并导致异ferlin缺乏小鼠出现他汀类药物抵抗性肌肉萎缩。
四肢带状肌营养不良(MD) 2B型(LGMD2B)和杜氏肌营养不良(DMD)分别是由Dysferlin和Dystrophin基因突变引起的。我们最近在典型的轻度dysferlin和dystrophin缺陷小鼠模型中证明,血浆胆固醇水平升高严重加剧了肌肉萎缩,DMD患者表现出以血浆胆固醇和甘油三酯升高为特征的原发性血脂异常。在这里,我们研究了LGMD2B的脂蛋白异常,以及他汀类药物治疗是否能保护dysferlin缺陷小鼠(Dysf)免受肌肉损伤。本文对LGMD2B患者和dysferlin-null (Dysf)小鼠的脂蛋白和肝酶进行分析。辛伐他汀在DMD小鼠模型中表现出抗肌肉萎缩作用,并纠正脂质代谢和内源性胆固醇合成关键标志物的异常表达,在Dysf小鼠中进行了测试。通过免疫组化和Western blot检测胆固醇信号通路评估肌肉损伤和纤维化。与健康对照相比,LGMD2B患者血清高密度脂蛋白胆固醇(HDL-C)水平降低,尽管没有肝功能障碍,但总胆固醇(CHOL)/HDL-C比率异常的发生率更高。虽然Dysf小鼠表现出CHOL和相关HDL-C和ldl - c相关部分的降低,但辛伐他汀治疗并不能防止股四头肌和三头肌肌肉群的肌肉萎缩,也不能纠正低密度脂蛋白受体(LDLR)和3-羟基-3-甲基戊二酰辅酶A还原酶(HMGCR)蛋白表达的异常。LGMD2B患者表现为血清HDL-C浓度降低,这是一种主要的代谢合并症,因此,他汀类药物治疗不太可能预防该人群的肌肉萎缩。我们建议与DMD一样,将LGMD2B视为一种新型的遗传性血脂异常。
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来源期刊
Skeletal Muscle
Skeletal Muscle CELL BIOLOGY-
CiteScore
9.10
自引率
0.00%
发文量
25
审稿时长
12 weeks
期刊介绍: The only open access journal in its field, Skeletal Muscle publishes novel, cutting-edge research and technological advancements that investigate the molecular mechanisms underlying the biology of skeletal muscle. Reflecting the breadth of research in this area, the journal welcomes manuscripts about the development, metabolism, the regulation of mass and function, aging, degeneration, dystrophy and regeneration of skeletal muscle, with an emphasis on understanding adult skeletal muscle, its maintenance, and its interactions with non-muscle cell types and regulatory modulators. Main areas of interest include: -differentiation of skeletal muscle- atrophy and hypertrophy of skeletal muscle- aging of skeletal muscle- regeneration and degeneration of skeletal muscle- biology of satellite and satellite-like cells- dystrophic degeneration of skeletal muscle- energy and glucose homeostasis in skeletal muscle- non-dystrophic genetic diseases of skeletal muscle, such as Spinal Muscular Atrophy and myopathies- maintenance of neuromuscular junctions- roles of ryanodine receptors and calcium signaling in skeletal muscle- roles of nuclear receptors in skeletal muscle- roles of GPCRs and GPCR signaling in skeletal muscle- other relevant aspects of skeletal muscle biology. In addition, articles on translational clinical studies that address molecular and cellular mechanisms of skeletal muscle will be published. Case reports are also encouraged for submission. Skeletal Muscle reflects the breadth of research on skeletal muscle and bridges gaps between diverse areas of science for example cardiac cell biology and neurobiology, which share common features with respect to cell differentiation, excitatory membranes, cell-cell communication, and maintenance. Suitable articles are model and mechanism-driven, and apply statistical principles where appropriate; purely descriptive studies are of lesser interest.
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