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.

Serum 25-Hydroxyvitamin D and Intact Parathyroid Hormone Influence Muscle Outcomes in Children and Adolescents

“…(34) In vitro studies further support this notion, showing alterations in calcium signaling pathways and myocellular gene expression after 25 (OH)D or 1,25(OH) 2 D exposure. (35)(36)(37) However, in agreement with the current study, improvements in serum 25(OH)D have also shown a neutral effect on muscle-related outcomes, including a lack of an effect on muscle strength, (38,39) muscle function, or the risk of falling. (40,41) Although alleviating vitamin D deficiency (<20 nmol/L) through supplementation improves muscle-related outcomes, (32)(33)(34)38,42,43) whether such effects occur in the absence of deficiency in both adolescents and adults (>20 nmol/L) is still unclear.…”

Reduction of mitochondria and up regulation of pyruvate dehydrogenase kinase 4 of skeletal muscle in patients with chronic kidney disease

“…Unfortunately, correlation analysis in the current study did not show a robust correlation between HGS and either serum 25(OH)VitD or 25(OH)VitD 3 levels. It was previously reported that 1α,25(OH) 2 VitD 3 , not the inactive form 25(OH) 2 VitD 3 , is positively correlated with limb strength in non‐CKD individuals . Also, the 25(OH)VitD 3 level can not directly reflect the 1α,25(OH) 2 VitD 3 level due to their different synthase and synthetic positions .…”

“…It was previously reported that 1α,25(OH) 2 VitD 3 , not the inactive form 25(OH) 2 VitD 3 , is positively correlated with limb strength in non-CKD individuals. 25 Also, the 25(OH)VitD 3 level can not directly reflect the 1α,25(OH) 2 VitD 3 level due to their different synthase and synthetic positions. 26 A direct study on serum 1α,25 (OH) 2 VitD 3 level and muscle strength was needed to confirm this relationship.…”

Vitamin D Deficiency and Sarcopenia in Older Persons

“…In fact, some studies, using specific and sensitive immunohistochemical assays, showed that the vitamin D receptor was undetectable in skeletal, cardiac and smooth muscle, suggesting an indirect involvement of the hormone on the muscles themselves [18]. On the other hands, subsequent studies revealed that VDR can be localized in the nucleus of human muscle cell lines, myoblasts [19] and adult skeletal muscle [20,21].…”