BackgroundADCK genes encode aarF domain‐containing mitochondrial kinases involved in coenzyme Q (CoQ) biosynthesis and regulation. Haploinsufficiency of ADCK2 in humans leads to adult‐onset physical incapacity with reduced mitochondrial CoQ levels in skeletal muscle, resulting in mitochondrial myopathy and alterations in fatty acid β‐oxidation. The sole current treatment for CoQ deficiencies is oral administration of CoQ10, which causes only partial recovery with postnatal treatment, underscoring the importance of early diagnosis for successful intervention.MethodsWe used Adck2 heterozygous mice to examine the influence of this gene on muscle structure, function and regeneration throughout development, growth and ageing. This investigation involved techniques including immunohistochemistry, analysis of CoQ levels, mitochondrial respiratory content, muscle transcriptome analysis and functional tests.ResultsWe demonstrated that Adck2 heterozygous mice exhibit defects from embryonic development, particularly in skeletal muscle (1102 genes deregulated). Adck2 heterozygous embryos were 7% smaller in size and displayed signs of delayed development. Prenatal administration of CoQ10 could mitigate these embryonic defects. Heterozygous Adck2 mice also showed a decrease in myogenic cell differentiation, with more severe consequences in ‘aged’ mice (41.63% smaller) (P < 0.01). Consequently, heterozygous Adck2 mice displayed accelerated muscle wasting associated with ageing in muscle structure (P < 0.05), muscle function (less grip strength capacity) (P < 0.001) and muscle mitochondrial respiration (P < 0.001). Furthermore, progressive CoQ10 administration conferred protective effects on mitochondrial function (P < 0.0001) and skeletal muscle (P < 0.05).ConclusionsOur work uncovered novel aspects of CoQ deficiencies, revealing defects during embryonic development in mammals for the first time. Additionally, we identified the gradual establishment and progression of the deleterious Adck2 mouse phenotype. Importantly, CoQ10 supplementation demonstrated a protective effect when initiated during development.

中文翻译：

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产前和进行中辅酶 Q10 给药可减轻线粒体疾病引起的肌肉功能障碍


背景ADCK基因编码包含aarF结构域的线粒体激酶，参与辅酶Q（CoQ）的生物合成和调节。人类 ADCK2 的单倍体不足会导致成年后的身体丧失能力，骨骼肌中线粒体 CoQ 水平降低，从而导致线粒体肌病和脂肪酸 β 氧化的改变。目前治疗 CoQ 缺乏症的唯一方法是口服 CoQ10，但产后治疗只能部分恢复，这凸显了早期诊断对于成功干预的重要性。方法我们使用 Adck2 杂合子小鼠来检测该基因对肌肉结构、功能和肌肉功能的影响。再生贯穿整个发育、生长和衰老过程。这项研究涉及的技术包括免疫组织化学、CoQ 水平分析、线粒体呼吸含量、肌肉转录组分析和功能测试。结果我们证明 Adck2 杂合子小鼠表现出胚胎发育缺陷，特别是骨骼肌（1102 个基因失调）。 Adck2 杂合胚胎尺寸小 7%，并显示出发育延迟的迹象。产前服用 CoQ10 可以减轻这些胚胎缺陷。杂合 Adck2 小鼠还表现出肌源性细胞分化的减少，“老年”小鼠的后果更为严重（小 41.63%）（P < 0.01）。因此，杂合 Adck2 小鼠在肌肉结构 (P < 0.05)、肌肉功能（握力能力较差）(P < 0.001) 和肌肉线粒体呼吸 (P < 0.001) 方面表现出与衰老相关的加速肌肉消耗。此外，渐进式 CoQ10 给药对线粒体功能 (P < 0.0001) 和骨骼肌 (P < 0.05) 具有保护作用。结论我们的工作揭示了 CoQ 缺陷的新方面，首次揭示了哺乳动物胚胎发育过程中的缺陷。此外，我们还发现了有害的 Adck2 小鼠表型的逐渐建立和发展。重要的是，在发育过程中开始补充辅酶 Q10 表现出保护作用。