Evidence for Vitamin D Receptor Expression and Direct Effects of 1α,25(OH)2D3 in Human Skeletal Muscle Precursor Cells

Olsson, Karin; Saini, Amarjit; Strömberg, Anna; Alam, Seher; Lilja, Mats; Rullman, Eric; Gustafsson, Thomas

doi:10.1210/en.2015-1685

Cited by 113 publications

(158 citation statements)

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“…4c). Indeed, Myostatin mRNA levels were reported to be unaltered in human muscle precursor cells upon 1α,25(OH) 2 D 3 treatment [14], suggesting that the modulation of Myostatin in VDR −/− muscles might be confined to the fiber alone.…”

Section: Discussionmentioning

confidence: 99%

“…However, signaling pathways that link the aberrations in myogenic gene expression and the progressive muscle atrophy observed postnatally in VDR −/− muscles have been unexplored. More importantly, recent evidence indicates that components of the vitamin D signaling cascade are expressed in human precursor cells and that the VDR in rodent quadriceps muscle responds to 1α,25(OH) 2 D 3 treatment [14, 15]. Nevertheless, mechanistic studies that account for the muscle atrophy observed in vitamin D-deficient individuals are lacking.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of Stat3 signaling ameliorates atrophy of the soleus muscles in mice lacking the vitamin D receptor

Gopinath

2017

Skeletal Muscle

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BackgroundAlthough skeletal muscle wasting has long been observed as a clinical outcome of impaired vitamin D signaling, precise molecular mechanisms that mediate the loss of muscle mass in the absence of vitamin D signaling are less clear. To determine the molecular consequences of vitamin D signaling, we analyzed the role of signal transducer and activator of transcription 3 (Stat3) signaling, a known contributor to various muscle wasting pathologies, in skeletal muscles.MethodsWe isolated soleus (slow) and tibialis anterior (fast) muscles from mice lacking the vitamin D receptor (VDR−/−) and used western blot analysis, quantitative RTPCR, and pharmacological intervention to analyze muscle atrophy in VDR−/− mice.ResultsWe found that slow and fast subsets of muscles of the VDR−/− mice displayed elevated levels of phosphorylated Stat3 accompanied by an increase in Myostatin expression and signaling. Consequently, we observed reduced activity of mammalian target of rapamycin (mTOR) signaling components, ribosomal S6 kinase (p70S6K) and ribosomal S6 protein (rpS6), that regulate protein synthesis and cell size, respectively. Concomitantly, we observed an increase in atrophy regulators and a block in autophagic gene expression. An examination of the upstream regulation of Stat3 levels in VDR−/− muscles revealed an increase in IL-6 protein expression in the soleus, but not in the tibialis anterior muscles. To investigate the involvement of satellite cells (SCs) in atrophy in VDR−/− mice, we found that there was no significant deficit in SC numbers in VDR−/− muscles compared to the wild type. Unlike its expression within VDR−/− fibers, Myostatin levels in VDR−/− SCs from bulk muscles were similar to those of wild type. However, VDR−/− SCs induced to differentiate in culture displayed increased p-Stat3 signaling and Myostatin expression. Finally, VDR−/− mice injected with a Stat3 inhibitor displayed reduced Myostatin expression and function and restored active p70S6K and rpS6 levels, resulting in an amelioration of loss of muscle mass in the soleus muscles.ConclusionsThe loss of muscle mass in slow muscles in the absence of vitamin D signaling is due to elevated levels of phosphorylated Stat3 that leads to an increase in Myostatin signaling, which in turn decreases protein synthesis and fiber size through the phosphorylation of p70S6K and rpS6, respectively.Electronic supplementary materialThe online version of this article (doi:10.1186/s13395-017-0121-2) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Inhibition of Stat3 signaling ameliorates atrophy of the soleus muscles in mice lacking the vitamin D receptor

Gopinath

2017

Skeletal Muscle

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“…Firstly, clinical signs of severe 25(OH)D deficiency (<25 nmol/L) [10] have been linked to myopathy, muscle pain and impaired gait, with amelioration by vitamin D supplementation [9]. Secondly, several studies have localised vitamin D receptor (VDR) in human muscle cell lines, myoblasts [11], and adult skeletal muscle [12,13], although opposing views have been published [14]. Thirdly, functional in vitro studies, have provided insights into the direct biological role of the active form of 25(OH)D, 1,25(OH2)D in regulation of genes and signalling pathways affecting calcium homeostasis, proliferation and differentiation of muscle cells [9], and positive correlation between 25(OH)D 3 and expression of 24 muscle genes at the mRNA level [13].…”

Section: Introductionmentioning

confidence: 99%

Vitamin D Status, Muscle Strength and Physical Performance Decline in Very Old Adults: A Prospective Study

et al. 2017

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Mixed reports exist about the role of 25-hydroxyvitamin D (25(OH)D) in muscle ageing and there are few prospective studies involving the very old (aged ≥ 85) who are at highest risk of low 25(OH)D, loss of muscle mass and strength, and physical performance decline. In the Newcastle 85+ Study (n = 845), we aimed to determine the association between 25(OH)D season-specific quartiles (hereafter SQ1–SQ4), grip strength (GS) and physical performance decline (Timed Up-and-Go Test, TUG) over 5 years using mixed models. In the time-only models with linear and quadratic slopes, SQ1 and SQ4 of 25(OH)D were associated with weaker GS initially in men (SQ1: β (SE) = −2.56 (0.96); SQ4: −2.16 (1.06)) and women (SQ1: −1.10 (0.52); SQ4: −1.28 (0.50)) (all p ≤ 0.04). In the fully adjusted models, only men in SQ1 had a significant annual decline in GS of 1.41 kg which accelerated over time (−0.40 (0.1)), (both p ≤ 0.003) compared with those in combined middle quartiles. Only women in SQ1 and SQ4 of 25(OH)D had worse TUG times initially, but the rate of TUG decline was not affected. Low baseline 25(OH)D may contribute to muscle strength decline in the very old and particularly in men.

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“…Recently, Al-Eisa et al evidenced a correlation between higher serum vitamin D levels and better physical muscle performance in physically active healthy older adults, probably by regulate on of the biosynthesis of creatine kinase, lactic acid dehydrogenase, troponin I, and hydroxyproline (AlEisa et al, 2016). Moreover, vitamin D receptor gene expression could have a role in muscle function, with a possible effect of this vitamin on proliferation and differentiation of muscle precursors (Bozsodi et al, 2016, Olsson et al, 2016. Some studies on the effect of this gene's variants on muscle strength are still contradictory, but individual genetic patterns might explain the inconsistency of our results on the association between vitamin D and muscle function (Bozsodi et al, 2016).…”

Section: Discussionmentioning

confidence: 81%

“…Recent studies hypothesized a negative effect of vitamin D deficit on the structure and function of the neuromuscular junction, causing lack of a stress response in muscles (Gifondorwa et al, 2016). Moreover, the vitamin D receptor gene has been indicated as a possible candidate gene in muscle function (Bozsodi et al, 2016;Olsson et al, 2016). The aims of this study were: i) to compare vitamin D blood levels in ALS patients with healthy subjects; ii) to correlate vitamin D blood levels with clinical and respiratory functions in enrolled patients; iii) to evaluate whether administration of vitamin D could modify the clinical progression of the disease.…”

Section: Introductionmentioning

confidence: 99%

Vitamin D in amyotrophic lateral sclerosis

Libonati¹,

Onesti²,

Gori³

et al. 2017

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SummaryVitamin D supplementation has been proposed as a potential treatment to delay amyotrophic lateral sclerosis (ALS) progression. The aims of this study were to compare retrospectively vitamin D blood levels in ALS patients with those in healthy subjects; to correlate vitamin D blood levels with clinical functions in patients; and to evaluate whether administration of vitamin D could modify the clinical progression of the disease. Vitamin D blood levels were evaluated in 57 ALS patients and in 57 healthy subjects. In the ALS patients the following clinical variables were evaluated every 3 months: Medical Research Council scale (MRC) score; revised ALS functional rating scale (ALSFRS-R) score; forced vital capacity (FVC). Twentyfour patients were treated with high doses of cholecalciferol. No significant differences were found between the vitamin D blood levels in the ALS patients (18.8 ± 12.2) and the healthy subjects (20.7 ± 10.1). The vitamin D levels in the ALS patientsdid not correlate with recorded clinical parameters. No clinical differences in terms of ALSFRS-R, MRC or FVC were found between the treated and the untreated patients over time. In ALS, as in other chronic neurological diseases, levels of vitamin D in blood appeared reduced, but no difference was found between the levels in ALS patients and in healthy subjects. Oral vitamin D supplementation in ALS patients was not associated with better prognosis in comparison with untreated ALS patients. Further prospective controlled studies are needed to clarify the effect of vitamin D on the progression of ALS disease.

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Evidence for Vitamin D Receptor Expression and Direct Effects of 1α,25(OH)2D3 in Human Skeletal Muscle Precursor Cells

Cited by 113 publications

References 40 publications

Inhibition of Stat3 signaling ameliorates atrophy of the soleus muscles in mice lacking the vitamin D receptor

Inhibition of Stat3 signaling ameliorates atrophy of the soleus muscles in mice lacking the vitamin D receptor

Vitamin D Status, Muscle Strength and Physical Performance Decline in Very Old Adults: A Prospective Study

Vitamin D in amyotrophic lateral sclerosis

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