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Clinical Trial
. 2017 Feb 15;12(2):e0170665.
doi: 10.1371/journal.pone.0170665. eCollection 2017.

25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 Exert Distinct Effects on Human Skeletal Muscle Function and Gene Expression

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Free PMC article
Clinical Trial

25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 Exert Distinct Effects on Human Skeletal Muscle Function and Gene Expression

Zaki K Hassan-Smith et al. PLoS One. .
Free PMC article

Abstract

Age-associated decline in muscle function represents a significant public health burden. Vitamin D-deficiency is also prevalent in aging subjects, and has been linked to loss of muscle mass and strength (sarcopenia), but the precise role of specific vitamin D metabolites in determining muscle phenotype and function is still unclear. To address this we quantified serum concentrations of multiple vitamin D metabolites, and assessed the impact of these metabolites on body composition/muscle function parameters, and muscle biopsy gene expression in a retrospective study of a cohort of healthy volunteers. Active serum 1,25-dihydroxyvitamin D3 (1α,25(OH)2D3), but not inactive 25-hydroxyvitamin D3 (25OHD3), correlated positively with measures of lower limb strength including power (rho = 0.42, p = 0.02), velocity (Vmax, rho = 0.40, p = 0.02) and jump height (rho = 0.36, p = 0.04). Lean mass correlated positively with 1α,25(OH)2D3 (rho = 0.47, p = 0.02), in women. Serum 25OHD3 and inactive 24,25-dihydroxyvitamin D3 (24,25(OH)2D3) had an inverse relationship with body fat (rho = -0.30, p = 0.02 and rho = -0.33, p = 0.01, respectively). Serum 25OHD3 and 24,25(OH)2D3 were also correlated with urinary steroid metabolites, suggesting a link with glucocorticoid metabolism. PCR array analysis of 92 muscle genes identified vitamin D receptor (VDR) mRNA in all muscle biopsies, with this expression being negatively correlated with serum 25OHD3, and Vmax, and positively correlated with fat mass. Of the other 91 muscle genes analysed by PCR array, 24 were positively correlated with 25OHD3, but only 4 were correlated with active 1α,25(OH)2D3. These data show that although 25OHD3 has potent actions on muscle gene expression, the circulating concentrations of this metabolite are more closely linked to body fat mass, suggesting that 25OHD3 can influence muscle function via indirect effects on adipose tissue. By contrast, serum 1α,25(OH)2D3 has limited effects on muscle gene expression, but is associated with increased muscle strength and lean mass in women. These pleiotropic effects of the vitamin D 'metabolome' on muscle function indicate that future supplementation studies should not be restricted to conventional analysis of the major circulating form of vitamin D, 25OHD3.

Conflict of interest statement

Competing Interests: Birmingham Health Partners does not represent a formal legal entity, but is a strategic alliance between the University of Birmingham, University Hospitals Birmingham, Birmingham Children's Hospital and Birmingham Women's Hospital. It therefore does not create any competing interests or financial affiliations, and we confirm that none of the authors are employed by Birmingham Health Partners. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. Multivariate visualisation of correlations between serum vitamin D metabolites.
Serum 25OHD3 (ng/ml), 3-Epi-25OHD3 (ng/ml), 24,25(OH)2D3 (ng/ml) and 1 α,25(OH)2D3 (pg/ml) represented as a scatterplot matrix (black circles female, red triangles male), with robust linear trendlines for bivariate regressions. The curve plots on the main diagonal are univariate histograms; the off-diagonal panels are bivariate scatterplots between variables labelled at the plot edges (e.g. the top row, second-from-right panel is 24,25(OH)2D3 versus 25OHD3).
Fig 2
Fig 2. Serum vitamin D metabolites and body composition parameters in women.
Serum (a) 25OHD3, (b) 24,25(OH)2D3 correlated negatively with body fat (rho = -0.30, p = 0.02 and rho = -0.33, p = 0.01, respectively), but not (c) 1α,25(OH)2D3 (rho = -0.06, p = 0.79). Conversely, lean mass correlated positively with (f) 1α,25(OH)2D3 (rho = 0.47, p = 0.02), but not (d) 25OHD3 or (e) 24,25(OH)2D3 (rho = 0.03, p = 0.81, and rho = 0.03, p = 0.80). Data were analysed by Spearman correlations (rho) with p values and line of best fit shown.
Fig 3
Fig 3. Serum vitamin D metabolites and urinary steroid metabolism in women.
Serum 25OHD3 and 24,25(OH)2D3 correlated negatively with urinary (tetrahydrocortisol+5α tetrahydrocortisol)/ tetrahydrocortisone ((THF+5αTHF)/THE ratios, and positively with urinary cortisol/cortisone (F/E) ratios. Data were analysed by Spearman correlations (rho) with p values and line of best fit shown.
Fig 4
Fig 4. Serum active vitamin D and muscle strength.
1α,25(OH)2D3 correlated positively with jump plate measures of lower limb strength (a) Pmax (maximal power), (b) Vmax (maximum velocity), (c) jump height, all on standing 2-legged jump (S2LJ). Data were analysed by Spearman correlations (rho) with line of best fit shown.
Fig 5
Fig 5. Expression of VDR mRNA in human muscle biopsies.
Relationship between muscle expression of VDR (RT-PCR ΔCt value) and: age; serum 25OHD3 concentrations (ng/ml); fat mass (Total mass, kg); Vmax (m/s). p values for linear regression analyses are shown and significant correlations are shown as solid lines. Data were analysed by Spearman correlations (rho) with line of best fit shown.

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