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Mechanical factors tune the sensitivity of mdx muscle to eccentric strength loss and its protection by antioxidant and calcium modulators.
Skeletal Muscle ( IF 5.3 ) Pub Date : 2020-02-01 , DOI: 10.1186/s13395-020-0221-2
Angus Lindsay 1, 2, 3 , Cory W Baumann 1 , Robyn T Rebbeck 2 , Samantha L Yuen 2 , William M Southern 2 , James S Hodges 4 , Razvan L Cornea 2 , David D Thomas 2 , James M Ervasti 2 , Dawn A Lowe 1
Affiliation  

Dystrophin deficiency sensitizes skeletal muscle of mice to eccentric contraction (ECC)-induced strength loss. ECC protocols distinguish dystrophin-deficient from healthy, wild type muscle, and test the efficacy of therapeutics for Duchenne muscular dystrophy (DMD). However, given the large lab-to-lab variability in ECC-induced strength loss of dystrophin-deficient mouse skeletal muscle (10–95%), mechanical factors of the contraction likely impact the degree of loss. Therefore, the purpose of this study was to evaluate the extent to which mechanical variables impact sensitivity of dystrophin-deficient mouse skeletal muscle to ECC. We completed ex vivo and in vivo muscle preparations of the dystrophin-deficient mdx mouse and designed ECC protocols within physiological ranges of contractile parameters (length change, velocity, contraction duration, and stimulation frequencies). To determine whether these contractile parameters affected known factors associated with ECC-induced strength loss, we measured sarcolemmal damage after ECC as well as strength loss in the presence of the antioxidant N-acetylcysteine (NAC) and small molecule calcium modulators that increase SERCA activity (DS-11966966 and CDN1163) or lower calcium leak from the ryanodine receptor (Chloroxine and Myricetin). The magnitude of length change, work, and stimulation duration ex vivo and in vivo of an ECC were the most important determinants of strength loss in mdx muscle. Passive lengthening and submaximal stimulations did not induce strength loss. We further showed that sarcolemmal permeability was associated with muscle length change, but it only accounted for a minimal fraction (21%) of the total strength loss (70%). The magnitude of length change also significantly influenced the degree to which NAC and small molecule calcium modulators protected against ECC-induced strength loss. These results indicate that ECC-induced strength loss of mdx skeletal muscle is dependent on the mechanical properties of the contraction and that mdx muscle is insensitive to ECC at submaximal stimulation frequencies. Rigorous design of ECC protocols is critical for effective use of strength loss as a readout in evaluating potential therapeutics for muscular dystrophy.

中文翻译:

机械因素可调节mdx肌肉对离心力损失的敏感性及其抗氧化剂和钙调节剂的保护作用。

肌营养不良蛋白缺乏症使小鼠的骨骼肌对离心收缩(ECC)引起的强度损失敏感。ECC协议将肌营养不良蛋白缺乏症与健康的野生型肌肉区分开来,并测试了杜氏肌营养不良症(DMD)的治疗功效。但是,鉴于ECC引起的肌营养不良蛋白缺陷型小鼠骨骼肌力量丧失的实验室间差异很大(10-95%),收缩的机械因素可能会影响其丧失程度。因此,本研究的目的是评估机械变量影响肌营养不良蛋白缺陷型小鼠骨骼肌对ECC敏感性的程度。我们完成了肌营养不良蛋白缺陷型mdx小鼠的离体和体内肌肉制备,并在生理范围内的收缩参数(长度变化,速度,收缩持续时间,和刺激频率)。为了确定这些收缩参数是否影响与ECC引起的力量丧失相关的已知因素,我们测量了ECC后的肌膜损伤以及在抗氧化剂N-乙酰半胱氨酸(NAC)和增加SERCA活性的小分子钙调节剂的存在下的力量丧失( DS-11966966和CDN1163)或更低的钙从雷诺丁受体(氯氧嘧啶和杨梅素)泄漏。ECC的离体和体内长度变化,功和刺激持续时间的大小是mdx肌肉力量丧失的最重要决定因素。被动延长和次最大刺激不会引起强度损失。我们进一步表明,肌膜通透性与肌肉长度变化有关,但仅占总力量损失(70%)的一小部分(21%)。长度变化的幅度也显着影响了NAC和小分子钙调节剂防止ECC引起的强度损失的程度。这些结果表明,ECC诱导的mdx骨骼肌力量丧失取决于收缩的机械特性,并且mdx肌肉在次最大刺激频率下对ECC不敏感。ECC协议的严格设计对于有效利用强度损失作为评估肌肉营养不良的潜在疗法的关键。这些结果表明,ECC诱导的mdx骨骼肌力量丧失取决于收缩的机械特性,并且mdx肌肉在次最大刺激频率下对ECC不敏感。ECC协议的严格设计对于有效利用强度损失作为评估肌肉营养不良的潜在疗法的关键。这些结果表明,ECC诱导的mdx骨骼肌力量丧失取决于收缩的机械特性,并且mdx肌肉在次最大刺激频率下对ECC不敏感。ECC协议的严格设计对于有效利用强度损失作为评估肌肉营养不良的潜在疗法的关键。
更新日期:2020-02-01
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