The vitamin D activator CYP27B1 is upregulated in muscle fibers in denervating disease and can track progression in amyotrophic lateral sclerosis.
The vitamin D activator CYP27B1 is upregulated in muscle fibers in denervating disease and can track progression in amyotrophic lateral sclerosis.
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维生素 D 激活剂 CYP27B1 在去神经疾病的肌纤维中表达上调，并且可以追踪肌萎缩侧索硬化症的进展。
DOI：
10.1016/j.jsbmb.2020.105650
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发表时间：
2020
期刊：
影响因子：
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通讯作者：
King,PeterH
中科院分区：
文献类型：
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作者：
Si,Ying;Kazamel,Mohamed;Kwon,Yuri;Lee,Ikjae;Anderson,Tina;Zhou,Siyu;Bamman,Marcas;Wiggins,Derek;Kwan,Thaddaeus;King,PeterH
细胞色素P450家族27亚家族B成员1（CYP 27 B1）的肾外表达已得到充分认可，反映了生理和病理条件下不同组织中内分泌/旁分泌维生素D信号传导的重要性。在先前的RNA测序项目中，我们鉴定了与正常对照相比，肌萎缩侧索硬化症（ALS）患者肌肉样本中CYP 27 B1 mRNA上调。我们的目标是：（1）在包括疾病对照在内的更大样本集中验证这一发现，（2）确定肌肉组织中哪种细胞类型表达CYP 27 B1蛋白，（3）将CYP 27 B1 mRNA表达与SOD 1G 93 AALS小鼠和ALS患者的疾病进展相关联。我们通过qPCR、蛋白质印迹和免疫组织化学评估了来自ALS、疾病对照（肌病和非ALS神经性疾病）、正常受试者的肌肉样本和来自SOD 1G 93 Amouse的肌肉样本库中的CYP 27 B1表达。8名ALS患者进行了前瞻性研究，为期6-12个月，进行了一系列肌肉活检。我们发现，CYP 27 B1 mRNA和蛋白水平显着增加ALS与正常和肌病肌肉样本。神经病变样本的CYP 27 B1 mRNA和蛋白表达增加，但水平低于ALS组。免疫组化显示CYP 27 B1主要定位于失神经支配的肌纤维。在SOD 1G 93 Amouse中，在症状前早期阶段的骨骼肌中检测到CYP 27 B1 mRNA和蛋白，并在终末期增加。在人体研究中，肌肉活检中CYP 27 B1 mRNA的增加与同一时期的疾病进展率相关。总之，我们首次表明，CYP 27 B1 mRNA和蛋白质表达在失神经支配疾病的肌纤维中升高，特别是ALS，其中mRNA水平可能作为跟踪疾病进展的替代标志物。它的上调可能反映了维生素D信号的局部扰动，进一步表征这一途径可能提供深入了解与肌肉去神经支配相关的潜在分子过程。
Extra-renal expression of Cytochrome P450 Family 27 Subfamily B Member 1 (CYP27B1) has been well recognized and reflects the importance of intracrine/paracrine vitamin D signaling in different tissues under physiological and pathological conditions. In a prior RNA sequencing project, we identified CYP27B1 mRNA as upregulated in muscle samples from patients with amyotrophic lateral sclerosis (ALS) compared to normal controls. Our aims here were: (1) to validate this finding in a larger sample set including disease controls, (2) to determine which cell type is expressing CYP27B1 protein in muscle tissue, (3) to correlate CYP27B1 mRNA expression with disease progression in the SOD1G93AALS mouse and in ALS patients. We assessed CYP27B1 expression by qPCR, western blot, and immunohistochemistry in a repository of muscle samples from ALS, disease controls (myopathy and non-ALS neuropathic disease), normal subjects, and muscle samples from the SOD1G93Amouse. Eight ALS patients were studied prospectively over 6–12 months with serial muscle biopsies. We found that CYP27B1 mRNA and protein levels were significantly increased in ALS versus normal and myopathy muscle samples. Neuropathy samples had increased CYP27B1 mRNA and protein expression but at a lower level than the ALS group. Immunohistochemistry showed that CYP27B1 localized to myofibers, especially those with features of denervation. In the SOD1G93Amouse, CYP27B1 mRNA and protein were detected in skeletal muscle in early pre-symptomatic stages and increased through end-stage. In the human study, increases in CYP27B1 mRNA in muscle biopsies correlated with disease progression rates over the same time period. In summary, we show for the first time that CYP27B1 mRNA and protein expression are elevated in muscle fibers in denervating disease, especially ALS, where mRNA levels can potentially serve as a surrogate marker for tracking disease progression. Its upregulation may reflect a local perturbation of vitamin D signaling, and further characterization of this pathway may provide insight into underlying molecular processes linked to muscle denervation.