Mitochondrial mutations alter endurance exercise response and determinants in mice.
Mitochondrial mutations alter endurance exercise response and determinants in mice.
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线粒体突变改变小鼠的耐力运动反应和决定因素。
DOI：
10.1073/pnas.2200549119
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发表时间：
2022-05-03
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
原发性线粒体疾病（PMDs）是最常见的先天性代谢紊乱疾病，估计每4200人中就有1人患病。耐力运动通常被认为可改善线粒体功能，但其在不同类型的PMDs中的应用指征尚不明确。我们确定了具有不同线粒体突变的小鼠的线粒体突变、耐力运动反应以及潜在分子通路之间的关系。这表明线粒体是运动能力和运动反应的关键调节因素。除了在ANT1缺陷小鼠中扩张型心肌病加重外，耐力运动在不同的线粒体突变小鼠中大多是有益的。因此，治疗性运动，特别是针对PMDs患者，应考虑患者的身体状况和线粒体遗传状况。
原发性线粒体疾病（PMDs）是一组异质性的代谢紊乱疾病，可由线粒体DNA（mtDNA）和核DNA（nDNA）基因中的数百种突变引起。目前的治疗方法有限，尽管运动训练是一种方法。已知耐力运动可改善健康受试者的线粒体功能，并降低患糖尿病或神经退行性疾病等继发性代谢紊乱的风险。然而，在PMDs中，耐力运动的益处尚不明确，运动可能对某些线粒体疾病有益，但对其他疾病则是禁忌的。在此，我们研究了耐力运动方案对具有不同线粒体突变的PMDs小鼠模型的影响。我们发现，虽然复合物I中的mtDNA ND6突变在运动反应中有所改善，但具有影响复合物IV的CO1突变的小鼠显示出的积极效果明显较少，而具有ND5复合物I突变的小鼠对运动完全没有反应。对于nDNA腺嘌呤核苷酸转位酶1（Ant1）缺陷的小鼠，耐力运动实际上加重了扩张型心肌病。将骨骼肌和心脏的基因表达谱与生理运动反应相关联，确定氧化磷酸化、氨基酸代谢、基质体（细胞外基质[ECM]）结构和细胞周期调节是运动反应中的关键通路。这强调了线粒体在决定运动能力和运动反应方面的关键作用。因此，耐力运动对PMDs的益处在很大程度上取决于潜在的突变，尽管我们的结果表明存在普遍的有益影响。
Primary mitochondrial diseases (PMDs) are the most prevalent inborn metabolic disorders, affecting an estimated 1 in 4,200 individuals. Endurance exercise is generally known to improve mitochondrial function, but its indication in the heterogeneous group of PMDs is unclear. We determined the relationship between mitochondrial mutations, endurance exercise response, and the underlying molecular pathways in mice with distinct mitochondrial mutations. This revealed that mitochondria are crucial regulators of exercise capacity and exercise response. Endurance exercise proved to be mostly beneficial across the different mitochondrial mutant mice with the exception of a worsened dilated cardiomyopathy in ANT1-deficient mice. Thus, therapeutic exercises, especially in patients with PMDs, should take into account the physical and mitochondrial genetic status of the patient. Primary mitochondrial diseases (PMDs) are a heterogeneous group of metabolic disorders that can be caused by hundreds of mutations in both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) genes. Current therapeutic approaches are limited, although one approach has been exercise training. Endurance exercise is known to improve mitochondrial function in heathy subjects and reduce risk for secondary metabolic disorders such as diabetes or neurodegenerative disorders. However, in PMDs the benefit of endurance exercise is unclear, and exercise might be beneficial for some mitochondrial disorders but contraindicated in others. Here we investigate the effect of an endurance exercise regimen in mouse models for PMDs harboring distinct mitochondrial mutations. We show that while an mtDNA ND6 mutation in complex I demonstrated improvement in response to exercise, mice with a CO1 mutation affecting complex IV showed significantly fewer positive effects, and mice with an ND5 complex I mutation did not respond to exercise at all. For mice deficient in the nDNA adenine nucleotide translocase 1 (Ant1), endurance exercise actually worsened the dilated cardiomyopathy. Correlating the gene expression profile of skeletal muscle and heart with the physiologic exercise response identified oxidative phosphorylation, amino acid metabolism, matrisome (extracellular matrix [ECM]) structure, and cell cycle regulation as key pathways in the exercise response. This emphasizes the crucial role of mitochondria in determining the exercise capacity and exercise response. Consequently, the benefit of endurance exercise in PMDs strongly depends on the underlying mutation, although our results suggest a general beneficial effect.
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