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Vitamin D Receptor and Vitamin D Action in Muscle Roger Bouillon, Evelien Gielen, and Dirk Vanderschueren Clinical and Experimental Endocrinology (R.B., D.V.), KU Leuven and department of Endocrinology, University Hospitals Leuven, B 3000 Leuven, Belgium; and Gerontology and Geriatrics (E.G.), KU Leuven and Department of Geriatrics, University Hospitals Leuven, B 3000 Leuven, Belgium

itamin D has been known for nearly a century to be essential for bone health because it can prevent and cure endemic rickets and osteomalacia (1–3). Currently, the complex implications of deficiency or excess vitamin D on bone modeling and remodeling are well documented by a wealth of preclinical and clinical studies (reviewed in 4). The vitamin D receptor (VDR) as well as the key activating (CYP27B1) or inactivating (CYP24A1) enzymes are, however, expressed in many cells. Moreover, a very large number of genes—from zebra fish up to mice and man—are under direct or indirect control of the active hormone, 1,25(OH)2D3. Therefore, it looks attractive to hypothesize that the vitamin D endocrine system would have many extraskeletal effects. Such hypothesis fits with the very broad spectrum of activity of most ligands of nuclear receptors (1–3). Poor vitamin D status has also been associated with most major diseases of mankind, ranging from immune diseases and infections, cancer, diabetes, and the metabolic syndrome, as well as cardiovascular risk factors and events, energy homeostasis, bile acid metabolism, to (last but not least) muscle function and falls (1, 3, 5). However, following an extensive evaluation of these data, the Institute of Medicine concluded, that “Scientific evidence indicates that calcium and vitamin D play key roles in bone health. The current evidence, however, does not support other benefits” and “There is inconsistent evidence that supplemental vitamin D reduces falls in postmenopausal women and older men” (6). This conclusion was highly debated because several meta-analyses concluded that vitamin D supplementation of elderly subjects decreased the risk of falls by approximately 20% and improved proximal muscle strength of severely vitamin D– deficient (serum 25OHD ⬍ 10 ng/ml) subjects (7, 8).

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Vitamin D’s direct action on muscle became doubtful when a careful analysis of VDR expression in adult human muscle as well as mouse skeletal and cardiac muscle, performed in H. DeLuca’s laboratory (9), vitamin D receptor showed only very low gene expression (10 000-fold lower than in the intestine) without detectable protein expression even with a highly specific anti-VDR antibody, in contrast with older publications using less stringent antibodies (9). Therefore, any potential effect of vitamin D metabolites on muscle could at most be indirect given that both genomic and potential nongenomic effects require the presence of VDR. In the current issue of Endocrinology, Girgis et al (10) demonstrate that VDR protein (using the same highly specific antibody) can be clearly demonstrated in adult mouse skeletal muscle, although only when using a hyperosmolar lysis buffer. Such buffer releases VDR from its tight binding to DNA, as it has been demonstrated previously that even unliganded VDR mainly resides in the nucleus. The gene and protein expression of VDR was higher in muscle cell precursors (in vitro) compared with adult mature muscle and was also higher in muscle from younger than in older animals (in vivo). Nevertheless, the expression was still several-fold lower in skeletal muscle than in the intestine. Moreover, the authors confirmed the expression as well as the functionality of cyp27b1 in muscle cell cultures. The activity of the vitamin D receptor was also confirmed because both 25OHD3 and 1,25(OH)2D3 stimulated the expression of VDR and Cyp24a1, both known targets of VDR action, as well as the uptake of 25OHD in muscle. Negative controls for all these end points were obtained in VDR-null mouse tissue. All the data are in line with decreasing VDR expression, as well as decreasing

ISSN Print 0013-7227 ISSN Online 1945-7170 Printed in U.S.A. Copyright © 2014 by the Endocrine Society Received July 14, 2014. Accepted July 29, 2014.

Abbreviation: VDR, vitamin D receptor.

For Counterpoint see page 3214; for article see page 3227

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doi: 10.1210/en.2014-1589

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number of VDR binding sites in the cistrome and decreasing transcriptome during maturation of other cells such as osteoblasts (11) and osteoclasts. Indeed, the expression of VDR is lost in multinucleated osteoclasts whereas 1,25(OH)2D3’s is a very potent stimulator of osteoclast progenitors (12). These novel data will clearly reopen the discussion on muscle as a potential target for vitamin D’s action. The gene and protein expression of VDR is also in line with several other in vitro studies. Indeed, 1,25(OH)2D3 decreased proliferation and enhanced differentiation of myocyte precursors, including the stimulation of follistatin and inhibition of myostatin (13) (Figure 1). Moreover, VDR-null mice show a clear muscle phenotype, with smaller muscle fiber size and abnormal expression of all major muscle-specific genes including myogenin, myoD, and Myf5 (14). Furthermore, cardioselective VDR deletion (15) also causes similar cardiac hypertrophy and fibrosis as in systemic VDR-null mice (Table 1). Finally, vitamin D deficiency accelerates muscle protein degradation by stimulation of the ubiquitin pathway in male rats (16). Do Girgis’ (10) observations in mouse muscle also apply to human skeletal, cardiac, and smooth muscle? Careful clinical observations indeed linked hypotonia, myop-

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athy, and especially proximal muscle weakness to rickets already in the early descriptions in the 17th century. More recently, muscle weakness was confirmed in subjects with inborn deficiency of CYP27B1 (hereditary pseudovitamin D deficiency rickets (18)) and in patients with severe chronic renal failure and deficiency of all vitamin D metabolites. Severe muscle weakness, up to the point of need for a wheel chair, also rapidly disappears when given 1,25(OH)2D3 (3). Randomized controlled trials, however, could not demonstrate beneficial effects of vitamin D supplementation on either grip strength or proximal muscle strength (except in patients with serum 25OHD levels ⬍ 10 ng/ml at baseline). Elegant in vivo 32P nuclear magnetic resonance spectroscopy data, however, showed more rapid energy (ATP) recovery after modest exercise, concomitant with correction of complaints of severe muscle weakness following vitamin D supplementation in deficient Asian United Kingdom residents (5, 19). Finally, the risk of falls could be reduced by approximately 20% after vitamin D supplementation of elderly, mostly vitamin D– deficient subjects, at least according to some (7, 8, 20) but not all meta-analyses (21). As for most ligands of nuclear receptors, too much may be equally deleterious as too little. Indeed an increased risk of falls and fractures

Figure 1. Muscle gene regulation by the vitamin D endocrine system as revealed by in vitro and in vivo rodent studies.

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Bouillon et al

Table 1.

Vitamin D Receptor and Vitamin D Action in Muscle

Endocrinology, September 2014, 155(9):3210 –3213

Overview of the Vitamin D Endocrine System and Muscle

Preclinical Data Molecular VDR gene and protein expression in adult muscle, albeit at much lower level than in the primary target tissue (intestine) Cellular (in vitro) 1,25(OH)2D3 inhibits proliferation and stimulates differentiation of early stage muscle cells by genomic and maybe also nongenomic actions In vivo * Impaired striated muscle maturation in global VDR null mice * Cardiac hypertrophy and fibrosis in cardiomyocyte-selective VDR null mice Clinical Observations Proximal muscle weakness in patients with vitamin D deficiency and chronic renal failure or in patients with inborn CYP27B1 deficiency: Rapid (days) correction by treatment with 1,25(OH)2D3 Many observational studies linking poor vitamin D status with muscle weakness or falls Randomized controlled vitamin D supplementation trials in vitamin D deficient human subjects showed more rapid recovery of ATP (energy) Randomized controlled vitamin D supplementation trials with inconsistent results on muscle strength Randomized controlled vitamin D supplementation trials with modest reduction in risk of fall of elderly mainly institutionalized subjects

was observed during the first 3 months following a yearly loading dose (500 000 IU of 25OHD3) (17). Therefore, muscle may indeed be a real target for vitamin D action but its mechanism of action may well be a combination of indirect [eg, myocardial dysfunction of vitamin D– deficient chicks could be corrected by calcium alone (22)], and direct genomic actions (23, 24) (Figure 1) or even nongenomic actions (24, 25). The study of Girgis et al (10) might generate more questions than answers. Protein expression of other nuclear receptors may also have to be reconsidered by using hyperosmolar conditions to better release such receptors from the nucleus, and this may be especially relevant for (un)liganded receptors residing permanently in the nucleus, or for clinical situations whereby receptor expression in cancer tissues is crucial for therapeutic decisions. A hyperosmolar lysis buffer was also needed to visualize heat shock proteins. Tissue-specific deletion of VDR or Cyp27B1, at early or late stage of muscle development or conditional postnatal deletion may help to clarify mechanism(s) of action of the vitamin D endocrine system. The Girgis study (10) also suggested that 1,25(OH)2D3 may stimulate the uptake of 25OHD in muscle, thereby addressing the intriguing question of the storage site of vitamin D (metabolites). Indeed, the summer accumulation of vitamin D apparently enables surviving lack of sunlight exposure during autumn and winter longer than expected from the short half-life of only two weeks of the serum pool of 25OHD.

Acknowledgments Address all correspondence and requests for reprints to: Roger Bouillon, Clinical and Experimental Endocrinology, KU Leuven,

Herestraat 49 ON1 Box 902, 3000 Leuven, Belgium. E-mail: [email protected] D.V. is a Senior Clinical Investigator funded by clinical research funds of the University Hospitals Leuven. The authors would like to acknowledge the support of grant G.0854.13N from the Research Foundation Flanders. Disclosure Summary: The authors have nothing to disclose.

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