title: 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 exert distinct effects on human skeletal muscle function and gene expression.
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.
authors.affiliation: Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, United Kingdom.|Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, United Kingdom.|Department of Endocrinology, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom.
authors.forename: Zaki K
authors.initials: ZK
authors.lastname: Hassan-Smith
authors.affiliation: Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Carl
authors.initials: C
authors.lastname: Jenkinson
authors.affiliation: Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, United Kingdom.|School of Mathematics, University of Birmingham, Birmingham, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Smith
authors.affiliation: Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Ivan
authors.initials: I
authors.lastname: Hernandez
authors.affiliation: Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Morgan
authors.affiliation: Department of Nuclear Medicine, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Crabtree
authors.affiliation: Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, United Kingdom.|Department of Endocrinology, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom.
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Gittoes
authors.affiliation: Department of Clinical Biochemistry, University Hospital South Manchester NHS Foundation Trust, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom.
authors.forename: Brian G
authors.initials: BG
authors.lastname: Keevil
authors.affiliation: Faculty of Medicine and Health, Worsley Building, University of Leeds, Leeds, United Kingdom.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Stewart
authors.affiliation: Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, United Kingdom.|Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, United Kingdom.
authors.forename: Martin
authors.identifier: http://orcid.org/0000-0001-5806-9690
authors.initials: M
authors.lastname: Hewison
mesh_terms: D000328:Adult; D000368:Aged; D002112:Calcifediol / Q000097:blood*; D002117:Calcitriol / Q000097:blood*; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000096:biosynthesis*; D053580:Muscle Strength / Q000502:physiology*; D018482:Muscle, Skeletal / Q000378:metabolism*
chemical_list: D009124:Muscle Proteins; D002117:Calcitriol; D002112:Calcifediol