Vitamin D Receptor Ablation and Vitamin D Deficiency Result in Reduced Grip Strength, Altered Muscle Fibers, and Increased Myostatin in Mice.
Vitamin D deficiency is associated with muscle weakness, pain, and atrophy. Serum vitamin D predicts muscle strength and age-related muscle changes. However, precise mechanisms by which vitamin D affects skeletal muscle are unclear. To address this question, this study characterizes the muscle phenotype and gene expression of mice with deletion of vitamin D receptor (VDRKO) or diet-induced vitamin D deficiency. VDRKO and vitamin D-deficient mice had significantly weaker grip strength than their controls. Weakness progressed with age and duration of vitamin D deficiency, respectively. Histological assessment showed that VDRKO mice had muscle fibers that were significantly smaller in size and displayed hyper-nuclearity. Real-time PCR also indicated muscle developmental changes in VDRKO mice with dysregulation of myogenic regulatory factors (MRFs) and increased myostatin in quadriceps muscle (>2-fold). Vitamin D-deficient mice also showed increases in myostatin and the atrophy marker E3-ubiqutin ligase MuRF1. As a potential explanation for grip strength weakness, both groups of mice had down-regulation of genes encoding calcium-handling and sarco-endoplasmic reticulum calcium transport ATPase (Serca) channels. This is the first report of reduced strength, morphological, and gene expression changes in VDRKO and vitamin D-deficient mice where confounding by calcium, magnesium, and phosphate have been excluded by direct testing. Although suggested in earlier in vitro work, this study is the first to report an in vivo association between vitamin D, myostatin, and the regulation of muscle mass. These findings support a direct role for vitamin D in muscle function and corroborate earlier work on the presence of VDR in this tissue.
Westmead Millennium Institute, 176 Hawkesbury Rd, Westmead, Sydney, NSW, 2145, Australia. c.girgis@usyd.edu.au.|Faculty of Medicine, University of Sydney, Sydney, NSW, Australia. c.girgis@usyd.edu.au.|Garvan Institute of Medical Research, Sydney, NSW, Australia. c.girgis@usyd.edu.au.
Christian M
CM
Girgis
Westmead Millennium Institute, 176 Hawkesbury Rd, Westmead, Sydney, NSW, 2145, Australia.|Garvan Institute of Medical Research, Sydney, NSW, Australia.
Kuan Minn
KM
Cha
Murdoch Childrens' Research Institute, Melbourne, VIC, Australia.
Peter J
PJ
Houweling
Westmead Millennium Institute, 176 Hawkesbury Rd, Westmead, Sydney, NSW, 2145, Australia.
Renuka
R
Rao
Garvan Institute of Medical Research, Sydney, NSW, Australia.
Nancy
N
Mokbel
Garvan Institute of Medical Research, Sydney, NSW, Australia.
Mike
M
Lin
Faculty of Medicine, University of Sydney, Sydney, NSW, Australia.|The Kolling Institute of Medical Research, Sydney, NSW, Australia.|Royal North Shore Hospital, Sydney, NSW, Australia.
Roderick J
RJ
Clifton-Bligh
Westmead Millennium Institute, 176 Hawkesbury Rd, Westmead, Sydney, NSW, 2145, Australia. jenny.gunton@sydney.edu.au.|Faculty of Medicine, University of Sydney, Sydney, NSW, Australia. jenny.gunton@sydney.edu.au.|Garvan Institute of Medical Research, Sydney, NSW, Australia. jenny.gunton@sydney.edu.au.|Department of Endocrinology and Diabetes, Westmead Hospital, Sydney, NSW, Australia. jenny.gunton@sydney.edu.au.|St Vincent's Clinical School, University of New South Wales, Sydney, NSW, Australia. jenny.gunton@sydney.edu.au.
Jenny E
JE
Gunton
D000818:Animals; D004195:Disease Models, Animal; D018737:Hand Strength / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology*; D055435:Myostatin / Q000096:biosynthesis*; D060888:Real-Time Polymerase Chain Reaction; D018167:Receptors, Calcitriol / Q000172:deficiency*; D014808:Vitamin D Deficiency / Q000378:metabolism / Q000503:physiopathology*
C525912:Mstn protein, mouse; D055435:Myostatin; D018167:Receptors, Calcitriol
Aging; Development; Skeletal muscle; Strength; Vitamin D; Vitamin D receptor