Deletion of vitamin D receptor gene in mice results in abnormal skeletal muscle development with deregulated expression of myoregulatory transcription factors

被引:329
作者
Endo, I
Inoue, D
Mitsui, T
Umaki, Y
Akaike, M
Yoshizawa, T
Kato, S
Matsumoto, T
机构
[1] Univ Tokushima, Grad Sch Med, Dept Med & Bioregulatory Sci, Tokushima 7708503, Japan
[2] Univ Tokyo, Inst Mol & Cellular Biosci, Tokyo 1130032, Japan
关键词
D O I
10.1210/en.2003-0502
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Although rachitic/osteomalacic myopathy caused by impaired vitamin D actions has long been described, the molecular pathogenesis remains elusive. To determine physiological roles of vitamin D actions through vitamin D receptor (VDR) in skeletal muscle development, we examined skeletal muscle in VDR gene deleted ( VDR -/-) mice, an animal model of vitamin D-dependent rickets type II, for morphological changes and expression of myoregulatory transcription factors and myosin heavy chain isoforms. We found that each muscle fiber was small and variable in size in hindlimb skeletal muscle from VDR -/- mice, although overall myocyte differentiation occurred normally. These abnormalities were independent of secondary metabolic changes such as hypocalcemia and hypophosphatemia, and were accompanied by aberrantly high and persistent expression of myf5, myogenin, E2A, and early myosin heavy chain isoforms, which are normally down-regulated at earlier stages. Moreover, treatment of VDR-positive myoblastic cells with 1,25(OH)(2)D-3 in vitro caused down-regulation of these factors. These results suggest that VDR plays a physiological role in skeletal muscle development, participating in temporally strict down-regulation of myoregulatory transcription factors. The present study can form a molecular basis of VDR actions on muscle and should help further establish the physiological roles of VDR in muscle development as well as pharmacological effects of vitamin D on muscle functions.
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页码:5138 / 5144
页数:7
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