The Role of the Vitamin D Receptor in Aging Skeletal Muscle and Inflammatory Response.
evidence suggests a strong and direct effect of vitamin D on skeletal muscle.
Observational studies demonstrate a positive association between serum 25-hydroxyvitamin
D (25OHD) concentration and muscle strength and function in older adults. In randomized
controlled trials, vitamin D supplementation in older adults increased muscle strength
and balance and reduced the risk of... read morefalls. The effects of vitamin D on aging muscle may
be mediated by its receptor (VDR). VDR is expressed in human skeletal muscle and when
bound to the active vitamin D metabolite, 1,25-dihydroxyvitamin-D3 (1,25(OH)2D3), it
regulates expression of genes that affect muscle cell differentiation and contractility.
At present, data on the relationship between 25OHD and VDR expression in human skeletal
muscle are limited. In Part 1 of this dissertation, we conducted three studies to
examine the effect of various metabolites of vitamin D on human skeletal muscle. These
studies examined 1) the effect of increasing concentrations of 1,25-dihydroxyvitamin D3
(1,25OH2D3) on VDR gene expression in human primary myoblasts, 2) the association
between serum 25-hydroxyvitamin D (25OHD) concentration and VDR protein concentration in
muscle of older adults, and 3) the effect of 16-week supplementation with vitamin D3 on
VDR gene expression in muscle of older women. We found that increasing 1,25OH2D3
concentration in human primary cell myoblasts significantly increased VDR mRNA
expression compared to controls. In older mobility-limited adults, serum 25OHD was
positively associated with VDR protein concentration. After 16 weeks of vitamin D3
supplementation, VDR mRNA expression was significantly greater compared to placebo in
muscle samples of older women. In Part 2 of this dissertation, we examined the role of
vitamin D in skeletal muscle inflammation using two models. First, we assessed the cross
sectional associations between 25OHD and/or VDR concentration with intramuscular
inflammatory markers (IL-6 and TNFa) and related signaling pathways (NFkB and p38 MAPK
phosphorylation). Second we investigated the longitudinal affects of 16 weeks of vitamin
D3 supplementation on alterations in skeletal muscle inflammatory markers (IL-6 and
TNFa). We found that intramuscular VDR protein concentration was positively associated
with intramuscular IL-6 gene expression but negatively associated with intramuscular
IL-6 protein concentration in older mobility-limited adults. However, intramuscular IL-6
gene expression was not altered after 16 weeks of vitamin D3 supplementation in older
mobility-limited women. Neither intramuscular VDR nor serum 25OHD was associated with
intramuscular TNFa. In conclusion, these data suggest 1) a direct relationship between
1,25OH2D3 and 25OHD concentrations with human intramuscular VDR mRNA and protein
concentration and 2) a subsequent association with intramuscular IL-6. Our findings
generate important hypotheses on the role of vitamin D in skeletal muscle; however,
larger randomized trials are needed to confirm our
Thesis (Ph.D.)--Tufts University, 2014.
Submitted to the Dept. of Biochemical and Molecular Nutrition.
Advisor: Roger Fielding.
Committee: Bess Dawson-Hughes, Alice Lichtenstein, and Lisa Ceglia.
Keywords: Nutrition, Physiology, and Aging.read less