Sarcopenia is an age-related disease characterized by a reduction in muscle mass, strength, and function and, therefore, a deterioration in skeletal muscle health and frailty. Although the cause of sarcopenia is still unknown and, thus, there is no treatment, increasing evidence suggests that chronodisruption, particularly alterations in Bmal1 clock gene, can lead to those deficits culminating in sarcopenia. To gain insight into the cause and mechanism of sarcopenia and the protective effect of a therapeutic intervention with exercise and/or melatonin, the gastrocnemius muscles of male and female skeletal muscle-specific and inducible Bmal1 knockout mice (iMS-Bmal1^−/−) were examined by phenotypic tests and light and electron microscopy. Our results revealed a disruption of the normal activity/rest rhythm, a drop in skeletal muscle function and mass, and increased frailty in male and female iMS-Bmal1^−/− animals compared to controls. A reduction in muscle fiber size and increased collagenous tissue were also detected, accompanied by reduced mitochondrial oxidative capacity and a compensatory shift towards a more oxidative fiber type. Electron microscopy further supports mitochondrial impairment in mutant mice. Melatonin and exercise ameliorated the damage caused by loss of Bmal1 in mutant mice, except for mitochondrial damage, which was worsened by the latter. Thus, iMS-Bmal1^−/− mice let us to identify Bmal1 deficiency as the responsible for the appearance of sarcopenia in the gastrocnemius muscle. Moreover, the results support the exercise and melatonin as therapeutic tools to counteract sarcopenia, by a mechanism that does not require the presence of Bmal1.

中文翻译：

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iMS-Bmal1−/− 小鼠表现出明显的肌少症症状，可通过运动和褪黑激素疗法抵消

肌肉减少症是一种与年龄相关的疾病，其特征是肌肉质量、力量和功能减少，从而导致骨骼肌健康恶化和虚弱。尽管肌肉减少症的病因仍不清楚，因此没有治疗方法，但越来越多的证据表明，时间紊乱，特别是Bmal1时钟基因的改变，可能导致这些缺陷，最终导致肌肉减少症。为了深入了解肌肉减少症的原因和机制以及运动和/或褪黑激素治疗干预的保护作用，对雄性和雌性骨骼肌特异性和可诱导的 Bmal1敲除小鼠 (iMS- Bmal1 ^−/− ) 的腓肠肌进行了研究。通过表型测试以及光学和电子显微镜检查。我们的结果显示，与对照组相比，雄性和雌性 iMS- Bmal1 ^−/−动物的正常活动/休息节律受到破坏，骨骼肌功能和质量下降，并且虚弱程度增加。还检测到肌纤维尺寸减小和胶原组织增加，伴随着线粒体氧化能力降低和向氧化性更强的纤维类型的代偿性转变。电子显微镜进一步支持突变小鼠的线粒体损伤。褪黑素和运动可以改善突变小鼠因Bmal1缺失而造成的损伤，但线粒体损伤除外，后者会加剧线粒体损伤。因此，iMS- Bmal1 ^−/−小鼠让我们确定Bmal1缺陷是导致腓肠肌出现肌肉减少症的原因。此外，结果支持运动和褪黑激素作为治疗工具来对抗肌肉减少症，其机制不需要Bmal1的存在。