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

Abstract

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.

Oral supplementation with 25(OH)D3 versus vitamin D3: Effects on 25(OH)D levels, lower extremity function, blood pressure, and markers of innate immunity

“…(40) Mice lacking the VDR show a skeletal muscle phenotype with smaller and variable muscle fibers and persistence of immature muscle gene expression during adult life. (34,41) Second, proximal muscle weakness is a prominent feature of the clinical syndrome of vitamin D deficiency. (42) Clinical findings in vitamin D deficiency myopathy include proximal muscle weakness, diffuse muscle pain, and gait impairments such as waddling way of walking.…”

Relationship Between Vitamin D and Muscle Size and Strength in Patients on Hemodialysis

“…This is not completely unexpected since vitamin D plays essential roles in regulating muscle contractility [7] and muscle growth [6]. Renal failure results in abnormalities in vitamin D metabolism due to the decline in proximal tubular production of 1α-hydroxylase.…”

“…Vitamin D plays an essential role in muscle growth and development [6] and in regulating muscle contractility [7]. Numerous studies in animals and humans have demonstrated the effects of vitamin D deficiency on various aspects of muscle cell function [8][9][10][11].…”

Генетический Полиморфизм Рецептора Витамина D Определяет Его Метаболизм И эффективность

“…В немногих экспериментальных исследованиях также показано значение РВД для респираторной системы: у мышей с отсутствием РВД авторы наблюдали раннее разви-тие ХОБЛ и эмфиземы, хронического воспаления и иммунной дисрегуляции, легочной деструкции, снижение в легких инфильтрации лимфоцитами и эозинофилами; однако при увеличении цитокинов и IgE наблюдали отсутствие гиперреактивного отве-та, в то же время терапия витамином D у этих мышей не влияла на течение у них БА [36]. Также показа-но влияние отсутствия РВД у мышей на редукцию в 20 % всех миофибрилл и нарушение в них регуля-торной mrf с ограничением роста и дифференциации миоцитов [37].…”