Yu Shuxiang, Ren Biqi, Chen Haiyun, Goltzman David, Yan Jianshe, Miao Dengshun
School of Medicine, Shanghai University Shanghai, China.
Research Center for Bone and Stem Cells, Department of Anatomy, Histology and Embryology, Key Laboratory for Aging & Disease, Nanjing Medical University Nanjing, China.
Am J Transl Res. 2021 Nov 15;13(11):12638-12649. eCollection 2021.
To determine if 1,25(OH)D deficiency can induce age-related sarcopenia, the skeletal muscular phenotype of male wild-type (WT) and Cyp27b1 knockout (KO) mice were compared at 3 and 6 months of age. We found that muscle mass, grip strength and muscle fiber size were significantly decreased in aging Cyp27b1 KO male mice. The expression levels of genes related to mitochondrial metabolic activity, and antioxidant enzymes including SOD1, catalase, Nqo1 and Gcs were significantly down-regulated in skeletal muscle tissue of Cyp27b1 KO male mice; in contrast, the percentage of p16 and p21 myofibers, and the expression of p16, p19, p21, p53, TNFα, IL6 and MMP3 at mRNA and/or protein levels were significantly increased. We then injected tibialis anterior muscle of WT and Cyp27b1 male mice with BaCl, and analyzed the regenerative ability of skeletal muscle cells 7 days later. The results revealed that the numbers of newly formed regenerating central nucleated fibers (CNF), the percentage of BrdU cells and the expression of MyoD, MyHC and Myf5 at mRNA levels were significantly down-regulated in the injured skeletal muscle tissue of Cyp27b1 mice. In summary, our studies indicate that 1,25(OH)D deficiency can result in the development of age-related sarcopenia by inducing oxidative stress, skeletal muscular cell senescence and SASP, and by inhibiting skeletal muscle regeneration. Cyp27b1 KO mice can therefore be used as an animal model of age-related sarcopenia in order to investigate the pathogenesis of age-related sarcopenia and potentially to test intervention measures for treatment of sarcopenia.
为了确定1,25(OH)D缺乏是否会诱发与年龄相关的肌肉减少症，我们比较了3月龄和6月龄雄性野生型（WT）小鼠和Cyp27b1基因敲除（KO）小鼠的骨骼肌表型。我们发现，衰老的Cyp27b1 KO雄性小鼠的肌肉质量、握力和肌纤维大小显著降低。在Cyp27b1 KO雄性小鼠的骨骼肌组织中，与线粒体代谢活性相关的基因以及包括超氧化物歧化酶1（SOD1）、过氧化氢酶、醌氧化还原酶1（Nqo1）和谷胱甘肽合成酶（Gcs）在内的抗氧化酶的表达水平显著下调；相反，p16和p21肌纤维的百分比以及p16、p19、p21、p53、肿瘤坏死因子α（TNFα）、白细胞介素6（IL6）和基质金属蛋白酶3（MMP3）在mRNA和/或蛋白质水平的表达显著增加。然后，我们向WT和Cyp27b1雄性小鼠的胫骨前肌注射氯化钡，并在7天后分析骨骼肌细胞的再生能力。结果显示，在Cyp27b1小鼠受损的骨骼肌组织中，新形成的再生中央有核纤维（CNF）数量、BrdU细胞百分比以及MyoD、肌球蛋白重链（MyHC）和Myf5在mRNA水平的表达均显著下调。总之，我们的研究表明，1,25(OH)D缺乏可通过诱导氧化应激、骨骼肌细胞衰老和衰老相关分泌表型（SASP）以及抑制骨骼肌再生，导致与年龄相关的肌肉减少症的发生。因此，Cyp27b1 KO小鼠可作为与年龄相关的肌肉减少症的动物模型，用于研究与年龄相关的肌肉减少症的发病机制，并有可能测试治疗肌肉减少症的干预措施。
