The Vitamin D Receptor (VDR) Is Expressed in Skeletal Muscle of Male Mice and Modulates 25-Hydroxyvitamin D (25OHD) Uptake in Myofibers

Abstract

Vitamin D deficiency is associated with a range of muscle disorders, including myalgia, muscle weakness, and falls. In humans, polymorphisms of the vitamin D receptor (VDR) gene are associated with variations in muscle strength, and in mice, genetic ablation of VDR results in muscle fiber atrophy and motor deficits. However, mechanisms by which VDR regulates muscle function and morphology remain unclear. A crucial question is whether VDR is expressed in skeletal muscle and directly alters muscle physiology. Using PCR, Western blotting, and immunohistochemistry (VDR-D6 antibody), we detected VDR in murine quadriceps muscle. Detection by Western blotting was dependent on the use of hyperosmolar lysis buffer. Levels of VDR in muscle were low compared with duodenum and dropped progressively with age. Two in vitro models, C2C12 and primary myotubes, displayed dose- and time-dependent increases in expression of both VDR and its target gene CYP24A1 after 1,25(OH)2D (1,25 dihydroxyvitamin D) treatment. Primary myotubes also expressed functional CYP27B1 as demonstrated by luciferase reporter studies, supporting an autoregulatory vitamin D-endocrine system in muscle. Myofibers isolated from mice retained tritiated 25-hydroxyvitamin D3, and this increased after 3 hours of pretreatment with 1,25(OH)2D (0.1nM). No such response was seen in myofibers from VDR knockout mice. In summary, VDR is expressed in skeletal muscle, and vitamin D regulates gene expression and modulates ligand-dependent uptake of 25-hydroxyvitamin D3 in primary myofibers.

Vitamin D, a modulator of musculoskeletal health in chronic kidney disease

“…37, 38 Genomic effects are delayed and include the gene expression of contractile proteins and myogenic transcription factors after interacting vitamin D with the VDR in skeletal muscle cells, which regulate muscle development and metabolism. Several studies confirm that VDR is expressed in muscle cells 9, 39. Although VDR is expressed at low levels in resting adult muscle, markedly VDR expression and 1α‐hydroxylase have been observed in neonatal muscle or following muscle injury, supporting the muscle capacity for local production of 1,25(OH) 2 D, and a developmental and regenerative role for vitamin D in this tissue 36, 40, 41…”

The relationship between vitamin D status and muscle strength in young healthy adults from sunny climate countries currently living in the northeast of Scotland

“…Early evidence supporting a role of vitamin D in muscle health can be found in patients with rickets and osteomalacia, who develop myopathy and muscle weakness which is reversible with vitamin D supplementation [2][3]. Further support for a role of vitamin D in muscle came from the identification of vitamin D receptors in skeletal muscle tissue, although this remains controversial [4][5][6]. The association between muscle strength and vitamin D status has been explored mainly in older populations for falls prevention and subsequent risk of [7].…”

Non-classical effects of vitamin D

“…Хотя в недавних исследованиях, использовавших им-муногистохимию с высокоспецифичными антителами, предполагается, что VDR не экспрессируется в скелет-ной, сердечной и гладкой мускулатуре [80], во множе-стве более ранних, а также в недавних исследованиях показано наличие VDR в птичьей, мышиной и человече-ской мышечной ткани с использованием иммуногисто-химии (в том числе с высокоспецифичными антителами), Вестерн-блота и определения мРНК в ПЦР [81]. Предпо-лагается, что VDR экспрессируется в очень низких ко-личествах в покоящихся мышцах, а активация экспрес-сии происходит в определенных условиях, например, при стрессе.…”

“…Предпо-лагается, что VDR экспрессируется в очень низких ко-личествах в покоящихся мышцах, а активация экспрес-сии происходит в определенных условиях, например, при стрессе. Исследование на моделях, использующих животных различного возраста, предполагает измене-ние экспрессии с возрастом и различную роль VDR в раз-вивающейся и зрелой мышечной ткани [81]; при воз-действии витамина D показано повышение экспрессии VDR в мышечной ткани человека [82], а также быстрые, нетранскрипционные эффекты в мышиной скелетной мускулатуре [83]. Предстоит определить, вызваны ли эффекты витамина D напрямую активацией VDR или опо-средованы изменениями абсорбции кальция, влияющи-ми на секрецию ПТГ и на внутриклеточные уровни каль-ция [61].…”