Impaired oxidative capacity and mitochondrial function contribute to the dystrophic pathology in muscles of Duchenne muscular dystrophy (DMD) patients and in relevant mouse models of the disease. Emerging evidence suggests an association between disrupted core clock expression and mitochondrial quality control, but this has not been established in muscles lacking dystrophin. We examined the diurnal regulation of muscle core clock and mitochondrial quality control expression in dystrophin-deficient C57BL/10ScSn-Dmd^mdx (mdx) mice, an established model of DMD. Male C57BL/10 (BL/10; n=18) and mdx mice (n=18) were examined every 4 hours beginning at the dark cycle. Throughout the entire light-dark cycle, extensor digitorum longus (EDL) muscles from mdx mice had decreased core clock mRNA expression (Arntl, Cry1, Cry2, Nr1d2; p<0.05) and disrupted mitochondrial quality control mRNA expression related to biogenesis (decreased; Ppargc1a, Esrra; p<0.05), fission (increased; Dnm1l; p<0.01), fusion (decreased; Opa1, Mfn1; p<0.05) and autophagy/mitophagy (decreased: Bnip3; p<0.05; increased: Becn1; p<0.05). Cosinor analysis revealed a decrease in the rhythmicity parameters mesor and amplitude for Arntl, Cry1, Cry2, Per2, and Nr1d1 (p<0.001) in mdx mice. Diurnal oscillations in Esrra, Sirt1, Map1lc3b and Sqstm1 were absent in mdx mice, along with decreased mesor and amplitude of Ppargc1a mRNA expression (p<0.01). The expression of proteins involved in mitochondrial biogenesis (decreased: PPARGC1A, p<0.05) and autophagy/mitophagy (increased: MAP1LC3BII, SQSTM1, BNIP3; p<0.05) were also dysregulated in tibialis anterior muscles of mdx mice. These findings suggest that dystrophin deficiency in mdx mice impairs the regulation of the core clock and mitochondrial quality control, with relevance to DMD and related disorders.

中文翻译：

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肌营养不良蛋白缺乏会破坏 mdx 小鼠的肌肉时钟表达和线粒体质量控制

氧化能力和线粒体功能受损导致 Duchenne 肌营养不良症 (DMD) 患者肌肉和该疾病相关小鼠模型的营养不良病理。新出现的证据表明，核心时钟表达中断与线粒体质量控制之间存在关联，但这在缺乏肌营养不良蛋白的肌肉中尚未得到证实。我们检查了肌营养不良蛋白缺乏的 ​​C57BL/10ScSn-Dmd ^mdx中肌肉核心时钟和线粒体质量控制表达的昼夜调节(mdx) 小鼠，已建立的 DMD 模型。从黑暗循环开始每 4 小时检查一次雄性 C57BL/10 (BL/10；n=18) 和 mdx 小鼠 (n=18)。在整个明暗周期中，来自 mdx 小鼠的指长伸肌 (EDL) 肌肉的核心时钟 mRNA 表达降低（Arntl、Cry1、Cry2、Nr1d2；p<0.05）并破坏与生物发生相关的线粒体质量控制 mRNA 表达（降低； Ppargc1a、Esrra；p<0.05）、裂变（增加；Dnm1l；p<0.01）、融合（减少；Opa1、Mfn1；p<0.05）和自噬/线粒体自噬（减少：Bnip3；p<0.05；p 增加：Becn1； <0.05）。余弦分析揭示了 mdx 小鼠中 Arntl、Cry1、Cry2、Per2 和 Nr1d1 的节律参数 mesor 和振幅降低（p<0.001）。在 mdx 小鼠中不存在 Esrra、Sirt1、Map1lc3b 和 Sqstm1 的昼夜振荡，随着 Ppargc1a mRNA 表达的中间和幅度降低（p <0.01）。在 mdx 小鼠胫骨前肌中，参与线粒体生物发生的蛋白质（降低：PPARGC1A，p<0.05）和自噬/线粒体自噬（增加：MAP1LC3BII、SQSTM1、BNIP3；p<0.05）的表达也失调。这些发现表明 mdx 小鼠的肌营养不良蛋白缺乏损害了核心时钟和线粒体质量控制的调节，与 DMD 和相关疾病有关。