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Vitamin D Receptor Ablation and Vitamin D Deficiency Result in Reduced Grip Strength, Altered Muscle Fibers, and Increased Myostatin in Mice

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Abstract

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.

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Acknowledgments

CMG received salary support from the NHMRC (National Health Medical and Research Council, Australia) as a post-doctoral early career fellow. JEG and RJC-B are also supported by NHMRC.

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Authors and Affiliations

  1. Westmead Millennium Institute, 176 Hawkesbury Rd, Westmead, Sydney, NSW, 2145, Australia

    Christian M. Girgis, Kuan Minn Cha, Renuka Rao & Jenny E. Gunton

  2. Faculty of Medicine, University of Sydney, Sydney, NSW, Australia

    Christian M. Girgis, Roderick J. Clifton-Bligh & Jenny E. Gunton

  3. Garvan Institute of Medical Research, Sydney, NSW, Australia

    Christian M. Girgis, Kuan Minn Cha, Nancy Mokbel, Mike Lin & Jenny E. Gunton

  4. Murdoch Childrens’ Research Institute, Melbourne, VIC, Australia

    Peter J. Houweling

  5. The Kolling Institute of Medical Research, Sydney, NSW, Australia

    Roderick J. Clifton-Bligh

  6. Royal North Shore Hospital, Sydney, NSW, Australia

    Roderick J. Clifton-Bligh

  7. Department of Endocrinology and Diabetes, Westmead Hospital, Sydney, NSW, Australia

    Jenny E. Gunton

  8. St Vincent’s Clinical School, University of New South Wales, Sydney, NSW, Australia

    Jenny E. Gunton

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  1. Christian M. Girgis
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Correspondence to Christian M. Girgis or Jenny E. Gunton.

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Christian M. Girgis, Kuan Minn Cha, Peter J. Houweling, Renuka Rao, Nancy Mokbel, Mike Lin, Roderick J. Clifton-Bligh and Jenny E. Gunton have no conflicts of interest or disclosures to report.

Human and Animal Rights and Informed Consent

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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Girgis, C.M., Cha, K.M., Houweling, P.J. et al. Vitamin D Receptor Ablation and Vitamin D Deficiency Result in Reduced Grip Strength, Altered Muscle Fibers, and Increased Myostatin in Mice. Calcif Tissue Int 97, 602–610 (2015). https://doi.org/10.1007/s00223-015-0054-x

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  • DOI: https://doi.org/10.1007/s00223-015-0054-x

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