Research Article: 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 exert distinct effects on human skeletal muscle function and gene expression

Date Published: February 15, 2017

Publisher: Public Library of Science

Author(s): Zaki K. Hassan-Smith, Carl Jenkinson, David J. Smith, Ivan Hernandez, Stuart A. Morgan, Nicola J. Crabtree, Neil J. Gittoes, Brian G. Keevil, Paul M. Stewart, Martin Hewison, Moray Campbell.


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.

Partial Text

The effects of vitamin D on calcium homeostasis and bone health are well established. In recent years there has been great interest in its non-skeletal actions, with growing evidence from epidemiological, basic and clinical studies that vitamin D status is associated with effects including those on muscle function, body fat, immunity and cardiovascular disease risk [1]. Myopathy has long-been recognised to co-exist with reduced bone mineralization in the severe vitamin D deficiency states of rickets and osteomalacia [2]. In view of the great public health burden of so-called ‘sarcopenia’ and age-associated declines in muscle strength and function, there is significant interest in whether vitamin D may have a role in improving the healthy lifespan. Recent meta-analyses indicate that vitamin D supplementation in deficient elderly individuals reduces risk of falls [3]. There is also some evidence of beneficial effects on muscle strength and physical performance, however this is limited by heterogeneity of study designs, so that current guidelines do not recommend vitamin D supplementation for this indication [4–6].

To date the majority of cross-sectional studies of vitamin D and muscle function have focused on circulating concentrations of 25OHD3, with some reports describing positive correlations with a heterogenous range of muscle function measures and others describing no significant associations, as outlined by Girgis and colleagues [1]. However, it is important to recognise that 25OHD3 is a relatively inactive form of vitamin D, so that its effects on target tissues are dependent on either systemic or localised metabolism to other vitamin D metabolites. The aim of the current study was to clarify the metabolic mechanisms that underpin the actions of vitamin D in human muscle.




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