Deletion of Vitamin D Receptor Gene in Mice Results in Abnormal Skeletal Muscle Development with Deregulated Expression of Myoregulatory Transcription Factors

• Published in: Endocrinology (Philadelphia) 2003-12, Vol.144 (12), p.5138-5144
• Main Authors: Endo, Itsuro, Inoue, Daisuke, Mitsui, Takao, Umaki, Yoshifumi, Akaike, Masashi, Yoshizawa, Tatsuya, Kato, Shigeaki, Matsumoto, Toshio
• Format: Article
• Language: English
• Subjects: Abnormalities; Animal models; Animals; Biological and medical sciences; Calciferol; Chromosome aberrations; Deficiency diseases; Deregulation; Disease Models, Animal; DNA-Binding Proteins; Down-regulation; Fundamental and applied biological sciences. Psychology; Gene deletion; Gene Expression Regulation, Developmental - drug effects; Gene Expression Regulation, Developmental - physiology; Gene regulation; Hypocalcemia; Hypophosphatemia; In Vitro Techniques; Isoforms; Medical genetics; Medical sciences; Mice; Mice, Knockout; Muscle Proteins - metabolism; Muscle, Skeletal - abnormalities; Muscle, Skeletal - cytology; Muscle, Skeletal - physiology; Muscles; Musculoskeletal system; Myocytes; Myogenic Regulatory Factor 5; Myogenin; Myogenin - metabolism; Myopathy; Myosin; Pathogenesis; Physiological effects; Physiology; Receptors; Receptors, Calcitriol - genetics; Receptors, Calcitriol - metabolism; Rickets; Rickets - genetics; Rickets - metabolism; Rickets - physiopathology; Skeletal muscle; Trans-Activators; Transcription factors; Transcription Factors - metabolism; Vertebrates: endocrinology; Vitamin D; Vitamin D - analogs & derivatives; Vitamin D - pharmacology; Vitamin D receptors; Vitamin D-dependent rickets
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2003-0502

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)2D3 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.