iMS-Bmal1-/- 小鼠表现出明显的肌肉疏松症状,而运动和褪黑激素疗法可抵消这种症状

IF 8.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Journal of Pineal Research Pub Date : 2023-09-13 DOI:10.1111/jpi.12912
José Fernández-Martínez, Yolanda Ramírez-Casas, Paula Aranda-Martínez, Alba López-Rodríguez, Ramy K. A. Sayed, Germaine Escames, Darío Acuña-Castroviejo
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摘要

肌肉疏松症是一种与年龄有关的疾病,其特点是肌肉质量、力量和功能下降,因此骨骼肌健康状况恶化,身体虚弱。虽然肌肉疏松症的病因尚不清楚,因此也没有治疗方法,但越来越多的证据表明,时序紊乱,特别是 Bmal1 时钟基因的改变,可导致这些缺陷,最终导致肌肉疏松症。为了深入了解肌肉疏松症的成因和机制,以及运动和/或褪黑激素的治疗干预的保护作用,我们通过表型测试、光镜和电子显微镜检查了雌雄骨骼肌特异性和诱导性 Bmal1 基因敲除小鼠(iMS-Bmal1-/-)的腓肠肌。结果显示,与对照组相比,iMS-Bmal1-/-雄性和雌性小鼠的正常活动/休息节律被打乱,骨骼肌功能和质量下降,体弱程度增加。此外,还发现肌肉纤维尺寸缩小,胶原组织增加,同时线粒体氧化能力降低,代偿性地转向氧化能力更强的纤维类型。电子显微镜进一步证实了突变小鼠线粒体功能受损。褪黑素和运动可改善突变小鼠因 Bmal1 缺失而造成的损伤,但线粒体损伤除外,后者会加重线粒体损伤。因此,iMS-Bmal1-/-小鼠让我们确定 Bmal1 缺乏是导致腓肠肌出现肌肉疏松症的原因。此外,研究结果还支持将运动和褪黑激素作为治疗工具,通过一种不需要 Bmal1 存在的机制来对抗肌少症。
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iMS-Bmal1−/− mice show evident signs of sarcopenia that are counteracted by exercise and melatonin therapies

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.

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来源期刊
Journal of Pineal Research
Journal of Pineal Research 医学-内分泌学与代谢
CiteScore
17.70
自引率
4.90%
发文量
66
审稿时长
1 months
期刊介绍: The Journal of Pineal Research welcomes original scientific research on the pineal gland and melatonin in vertebrates, as well as the biological functions of melatonin in non-vertebrates, plants, and microorganisms. Criteria for publication include scientific importance, novelty, timeliness, and clarity of presentation. The journal considers experimental data that challenge current thinking and welcomes case reports contributing to understanding the pineal gland and melatonin research. Its aim is to serve researchers in all disciplines related to the pineal gland and melatonin.
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