Simvastatin does not alleviate muscle pathology in a mouse model of Duchenne muscular dystrophy.

IF 5.3 2区医学 Q2 CELL BIOLOGY

Skeletal Muscle Pub Date : 2021-09-03 DOI:10.1186/s13395-021-00276-3

Olga Mucha, Paulina Podkalicka, Katarzyna Kaziród, Emilia Samborowska, Józef Dulak, Agnieszka Łoboda

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引用次数: 12

Abstract

Background: Duchenne muscular dystrophy (DMD) is an incurable disease, caused by the mutations in the DMD gene, encoding dystrophin, an actin-binding cytoskeletal protein. Lack of functional dystrophin results in muscle weakness, degeneration, and as an outcome cardiac and respiratory failure. As there is still no cure for affected individuals, the pharmacological compounds with the potential to treat or at least attenuate the symptoms of the disease are under constant evaluation. The pleiotropic agents, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, known as statins, have been suggested to exert beneficial effects in the mouse model of DMD. On the other hand, they were also reported to induce skeletal-muscle myopathy. Therefore, we decided to verify the hypothesis that simvastatin may be considered a potential therapeutic agent in DMD.

Methods: Several methods including functional assessment of muscle function via grip strength measurement, treadmill test, and single-muscle force estimation, enzymatic assays, histological analysis of muscle damage, gene expression evaluation, and immunofluorescence staining were conducted to study simvastatin-related alterations in the mdx mouse model of DMD.

Results: In our study, simvastatin treatment of mdx mice did not result in improved running performance, grip strength, or specific force of the single muscle. Creatine kinase and lactate dehydrogenase activity, markers of muscle injury, were also unaffected by simvastatin delivery in mdx mice. Furthermore, no significant changes in inflammation, fibrosis, and angiogenesis were noted. Despite the decreased percentage of centrally nucleated myofibers in gastrocnemius muscle after simvastatin delivery, no changes were noticed in other regeneration-related parameters. Of note, even an increased rate of necrosis was found in simvastatin-treated mdx mice.

Conclusion: In conclusion, our study revealed that simvastatin does not ameliorate DMD pathology.

Abstract Image

查看原文本刊更多论文

辛伐他汀不能缓解杜氏肌营养不良小鼠模型的肌肉病理。

背景:杜氏肌营养不良症(DMD)是一种无法治愈的疾病，由编码肌动蛋白结合细胞骨架蛋白-肌营养不良蛋白的DMD基因突变引起。缺乏功能性肌营养不良蛋白会导致肌肉无力、变性，最终导致心脏和呼吸衰竭。由于仍然无法治愈受影响的个体，因此正在不断评估有可能治疗或至少减轻该疾病症状的药理学化合物。多效药物，3-羟基-3-甲基戊二酰辅酶A (HMG-CoA)还原酶抑制剂，被称为他汀类药物，已被认为在小鼠DMD模型中发挥有益作用。另一方面，据报道它们也会诱发骨骼肌肌病。因此，我们决定验证辛伐他汀可能被认为是DMD的潜在治疗剂的假设。方法:通过握力测量、跑步机试验、单肌力评估、酶分析、肌肉损伤组织学分析、基因表达评估和免疫荧光染色等方法对mdx小鼠DMD模型进行辛伐他汀相关改变的研究。结果:在我们的研究中，辛伐他汀治疗mdx小鼠并没有导致跑步性能、握力或单个肌肉比力的改善。肌酸激酶和乳酸脱氢酶活性，肌肉损伤的标志，也不受辛伐他汀给药mdx小鼠的影响。此外，炎症、纤维化和血管生成未见明显变化。尽管辛伐他汀给药后腓肠肌中央有核肌纤维百分比下降，但其他与再生相关的参数未见变化。值得注意的是，在辛伐他汀治疗的mdx小鼠中，甚至发现坏死率增加。结论:本研究表明辛伐他汀对DMD病理没有改善作用。

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来源期刊

Skeletal Muscle CELL BIOLOGY-

CiteScore

9.10

自引率

0.00%

发文量

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.