Abstract
ObjectiveVitamin D deficiency is common among older adults and has been linked to muscle weakness. Vitamin D supplementation has been proposed as a strategy to improve muscle function in older adults. The aim of this study was to investigate the effect of calcifediol (25-hydroxycholecalciferol) on whole genome gene expression in skeletal muscle of vitamin D deficient frail older adults.MethodsA double-blind placebo-controlled trial was conducted in vitamin D deficient frail older adults (aged above 65), characterized by blood 25-hydroxycholecalciferol concentrations between 20 and 50 nmol/L. Subjects were randomized across the placebo group and the calcifediol group (10 μg per day). Muscle biopsies were obtained before and after 6 months of calcifediol (n = 10) or placebo (n = 12) supplementation and subjected to whole genome gene expression profiling using Affymetrix HuGene 2.1ST arrays.ResultsExpression of the vitamin D receptor gene was virtually undetectable in human skeletal muscle biopsies, with Ct values exceeding 30. Blood 25-hydroxycholecalciferol levels were significantly higher after calcifediol supplementation (87.3 ± 20.6 nmol/L) than after placebo (43.8 ± 14.1 nmol/L). No significant difference between treatment groups was observed on strength outcomes. The whole transcriptome effects of calcifediol and placebo were very weak, as indicated by the fact that correcting for multiple testing using false discovery rate did not yield any differentially expressed genes using any reasonable cut-offs (all q-values ~ 1). P-values were uniformly distributed across all genes, suggesting that low p-values are likely to be false positives. Partial least squares-discriminant analysis and principle component analysis was unable to separate treatment groups.ConclusionCalcifediol supplementation did not significantly affect the skeletal muscle transcriptome in frail older adults. Our findings indicate that vitamin D supplementation has no effects on skeletal muscle gene expression, suggesting that skeletal muscle may not be a direct target of vitamin D in older adults.Trial registrationThis study was registered at clinicaltrials.gov as NCT02349282 on January 28, 2015.
Highlights
Muscle weakness and muscle loss increase with age, potentially leading to increased risk of falls, frailty and loss of independence among older adults [1]
Vitamin D status and muscle strength Calcifediol supplementation led to significant increases in total 25(OH)D3 and 24,25(OH2)D3 levels compared to placebo (Table 1)
The Ct values for qPCR amplification of vitamin D receptor (VDR) in the muscle biopsies were above 30 (Fig. 1), suggesting that VDR is expressed at very low levels in human skeletal muscle
Summary
Muscle weakness and muscle loss increase with age, potentially leading to increased risk of falls, frailty and loss of independence among older adults [1]. One of the factors that may influence muscle health is vitamin D. Many older adults are deficient or insufficient in vitamin D [2, 3]. In a recent study in 4495 European individuals aged > 65 years, vitamin D deficiency (serum 25-hydroxyvitamin D 25–50 nmol/L) and vitamin D insufficiency (50–75 nmol/L) were found in 41 and 33% of the population, respectively [3]. Various observational studies have found associations between vitamin D deficiency and impaired muscle function and/or physical performance in older adults [4,5,6,7,8]. Vitamin D supplementation has been proposed as a strategy to improve muscle function [9]
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