Fiuza-Luces Carmen, Valenzuela Pedro L, Laine-Menéndez Sara, Fernández-de la Torre Miguel, Bermejo-Gómez Verónica, Rufián-Vázquez Laura, Arenas Joaquín, Martín Miguel A, Lucia Alejandro, Morán María
Mitochondrial and Neuromuscular Diseases Laboratory, Research Institute of Hospital 12 de Octubre (i+12), Madrid, Spain.
Physiology Unit, Systems Biology Department, University of Alcalá, Madrid, Spain.
Front Neurol. 2019 Jul 25;10:790. doi: 10.3389/fneur.2019.00790. eCollection 2019.
Mitochondrial diseases (MD) are among the most prevalent neuromuscular disorders. Unfortunately, no curative treatment is yet available. This study analyzed the effects of exercise training in an animal model of respiratory chain complex I deficiency, the Harlequin () mouse, which replicates the clinical features of this condition. Male heterozygous Harlequin (/Y) mice were assigned to an "exercise" ( = 10) or a "sedentary" control group ( = 11), with the former being submitted to an 8 week combined exercise training intervention (aerobic + resistance training performed five times/week). Aerobic fitness, grip strength, and balance were assessed at the beginning and at the end of the intervention period in all the mice. Muscle biochemical analyses (with results expressed as percentage of reference data from age/sex-matched sedentary wild-type mice [ = 12]) were performed at the end of the aforementioned period for the assessment of major molecular signaling pathways involved in muscle anabolism (mTOR activation) and mitochondrial biogenesis (proliferator activated receptor gamma co-activator 1α [PGC-1α] levels), and enzyme activity and levels of respiratory chain complexes, and antioxidant enzyme levels. Exercise training resulted in significant improvements in aerobic fitness (-33 ± 13 m and 83 ± 43 m for the difference post- vs. pre-intervention in total distance covered in the treadmill tests in control and exercise group, respectively, = 0.014) and muscle strength (2 ± 4 g vs. 17 ± 6 g for the difference post vs. pre-intervention, = 0.037) compared to the control group. Higher levels of ribosomal protein S6 kinase beta-1 phosphorylated at threonine 389 (156 ± 30% vs. 249 ± 30%, = 0.028) and PGC-1α (82 ± 7% vs. 126 ± 19% = 0.032) were observed in the exercise-trained mice compared with the control group. A higher activity of respiratory chain complexes I (75 ± 4% vs. 95 ± 6%, = 0.019), III (79 ± 5% vs. 97 ± 4%, = 0.031), and V (77 ± 9% vs. 105 ± 9%, = 0.024) was also found with exercise training. Exercised mice presented with lower catalase levels (204 ± 22% vs. 141 ± 23%, = 0.036). In a mouse model of MD, a training intervention combining aerobic and resistance exercise increased aerobic fitness and muscle strength, and mild improvements were found for activated signaling pathways involved in muscle mitochondrial biogenesis and anabolism, OXPHOS complex activity, and redox status in muscle tissue.
线粒体疾病（MD）是最常见的神经肌肉疾病之一。不幸的是，目前尚无治愈性治疗方法。本研究分析了运动训练对呼吸链复合体I缺乏症动物模型——丑角（）小鼠的影响，该模型复制了这种疾病的临床特征。将雄性杂合丑角（/Y）小鼠分为“运动”组（ = 10）或“久坐”对照组（ = 11），前者接受为期8周的联合运动训练干预（有氧运动+阻力训练，每周进行5次）。在干预期开始和结束时，对所有小鼠的有氧适能、握力和平衡能力进行评估。在上述时期结束时，进行肌肉生化分析（结果以年龄/性别匹配的久坐野生型小鼠[ = 12]的参考数据百分比表示），以评估参与肌肉合成代谢（mTOR激活）和线粒体生物发生（增殖激活受体γ共激活因子1α[PGC-1α]水平）的主要分子信号通路、呼吸链复合体的酶活性和水平以及抗氧化酶水平。与对照组相比，运动训练使有氧适能（对照组和运动组在跑步机测试中干预后与干预前总距离覆盖的差异分别为-33±13米和83±43米， = 0.014）和肌肉力量（干预后与干预前的差异分别为2±4克和17±6克， = 0.037）有显著改善。与对照组相比，运动训练的小鼠中苏氨酸389磷酸化的核糖体蛋白S6激酶β-1（156±30%对249±30%， = 0.028）和PGC-1α（82±7%对126±19%， = 0.032）水平更高。运动训练还使呼吸链复合体I（75±4%对95±6%， = 0.019）、III（79±5%对97±4%， = 0.031）和V（77±9%对105±9%， = 0.024）的活性更高。运动小鼠的过氧化氢酶水平较低（204±22%对141±23%， = 0.036）。在MD小鼠模型中，结合有氧运动和阻力运动的训练干预提高了有氧适能和肌肉力量，并且在参与肌肉线粒体生物发生和合成代谢的激活信号通路、氧化磷酸化复合体活性以及肌肉组织的氧化还原状态方面有轻微改善。
