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16-11-2022 | Original Article

Effect of vitamin D₃ vs. calcifediol on VDR concentration and fiber size in skeletal muscle

Authors: Lisa Ceglia, Donato A. Rivas, Mathias Schlögl, Grace B. Fielding, Andreas Egli, Heike A. Bischoff-Ferrari, Bess Dawson-Hughes

Published in: Journal of Bone and Mineral Metabolism | Issue 1/2023

Abstract

Introduction

This study sought to examine the effect of vitamin D₃ (VD₃) 3200 IU/d, calcifediol (HyD) 20mcg/d, or placebo on intramyonuclear vitamin D receptor (VDR) concentration, muscle fiber cross-sectional area (FCSA), and muscle satellite cell activation.

Materials and methods

It was conducted on a subset of the VD₃ (n = 12), HyD (n = 11), and placebo (n = 13) groups who participated in the 6-month randomized controlled HyD Osteopenia Study in postmenopausal women. Baseline and 6-month vastus lateralis muscle cross sections were probed for VDR, fiber type I and II, and PAX7 (satellite cell marker) using immunofluorescence.

Results

Baseline mean ± SD age was 61 ± 4 years and serum 25-hydroxyvitamin D (25OHD) level was 55.1 ± 22.8 nmol/L. Baseline characteristics did not differ significantly by group. Six-month mean ± SD 25OHD levels were 138.7 ± 22.2 nmol/L (VD₃), 206.8 ± 68.8 nmol/L (HyD), and 82.7 ± 36.1 nmol/L (placebo), ANOVA P < 0.001. There were no significant group differences in 6-month change in VDR concentration (ANOVA P = 0.227). Mean ± SD percent 6-month changes in type I FCSA were 20.5 ± 32.7% (VD₃), − 6.6 ± 20.4% (HyD), and − 0.3 ± 14.0% (placebo, ANOVA P = 0.022). Type II FCSA or PAX7 concentration did not change significantly by group (all P > 0.358).

Conclusion

This study demonstrated no significant change in intramyonuclear VDR in response to either form of vitamin D vs. placebo. Type I FCSA significantly increased with VD₃, but not with HyD at 6 months. As type I fibers are more fatigue resistant than type II, enlargement in type I suggests potential for improved muscle endurance. Although HyD resulted in the highest 25OHD levels, no skeletal muscle benefits were noted at these high levels.

Clinical trial

NCT02527668.

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Braga M, Simmons Z, Norris KC, Ferrini MG, Artaza JN (2017) Vitamin D induces myogenic differentiation in skeletal muscle derived stem cells. Endocr Connect 6:139–150. https://doi.org/10.1530/EC-17-0008CrossRef

Garcia LA, Ferrini MG, Norris KC, Artaza JN (2013) 1,25(OH)(2)vitamin D(3) enhances myogenic differentiation by modulating the expression of key angiogenic growth factors and angiogenic inhibitors in C(2)C(12) skeletal muscle cells (in eng). J Steroid Biochem Mol Biol 133:1–11. https://doi.org/10.1016/j.jsbmb.2012.09.004CrossRef

Girgis CM, Clifton-Bligh RJ, Mokbel N, Cheng K, Gunton JE (2014) Vitamin D signaling regulates proliferation, differentiation, and myotube size in C2C12 skeletal muscle cells. Endocrinology 155:347–357. https://doi.org/10.1210/en.2013-1205CrossRef

Girgis CM (2020) Vitamin D and skeletal muscle: emerging roles in development, anabolism and repair. Calcif Tissue Int 106:47–57. https://doi.org/10.1007/s00223-019-00583-4CrossRef

Latham CM, Brightwell CR, Keeble AR, Munson BD, Thomas NT, Zagzoog AM, Fry CS, Fry JL (2021) Vitamin D promotes skeletal muscle regeneration and mitochondrial health. Front Physiol 12:660498. https://doi.org/10.3389/fphys.2021.660498CrossRef

Bischoff HA, Borchers M, Gudat F, Duermueller U, Theiler R, Stahelin HB, Dick W (2001) In situ detection of 1,25-dihydroxyvitamin D3 receptor in human skeletal muscle tissue (in eng). Histochem J 33:19–24CrossRef

Buitrago C, Boland R (2010) Caveolae and caveolin-1 are implicated in 1alpha,25(OH)(2)-vitamin D(3)-dependent modulation of Src, MAPK cascades and VDR localization in skeletal muscle cells (in Eng). J Steroid Biochem Mol Biol. https://doi.org/10.1016/j.jsbmb.2010.03.002CrossRef

Wang Y, DeLuca HF (2011) Is the vitamin d receptor found in muscle? (in eng). Endocrinology 152:354–363. https://doi.org/10.1210/en.2010-1109CrossRef

Ceglia L, da Silva MM, Park LK, Morris E, Harris SS, Bischoff-Ferrari HA, Fielding RA, Dawson-Hughes B (2010) Multi-step immunofluorescent analysis of vitamin D receptor loci and myosin heavy chain isoforms in human skeletal muscle (in eng). J Mol Histol 41:137–142. https://doi.org/10.1007/s10735-010-9270-xCrossRef

10.

Girgis CM, Mokbel N, Cha KM, Houweling PJ, Abboud M, Fraser DR, Mason RS, Clifton-Bligh RJ, Gunton JE (2014) The vitamin D receptor (VDR) is expressed in skeletal muscle of male mice and modulates 25-hydroxyvitamin D (25OHD) uptake in myofibers. Endocrinology 155:3227–3237. https://doi.org/10.1210/en.2014-1016CrossRef

11.

Olsson K, Saini A, Stromberg A, Alam S, Lilja M, Rullman E, Gustafsson T (2016) Evidence for vitamin D receptor expression and direct effects of 1α,25(OH)2D3 in human skeletal muscle precursor cells. Endocrinology 157:98–111. https://doi.org/10.1210/en.2015-1685CrossRef

12.

Chen S, Villalta SA, Agrawal DK (2016) FOXO1 mediates vitamin D deficiency-induced insulin resistance in skeletal muscle. J Bone Miner Res 31:585–595. https://doi.org/10.1002/jbmr.2729CrossRef

13.

Girgis CM, Cha KM, So B, Tsang M, Chen J, Houweling PJ, Schindeler A, Stokes R, Swarbrick MM, Evesson FJ, Cooper ST, Gunton JE (2019) Mice with myocyte deletion of vitamin D receptor have sarcopenia and impaired muscle function. J Cachexia Sarcopenia Muscle 10:1228–1240. https://doi.org/10.1002/jcsm.12460CrossRef

14.

Bass JJ, Nakhuda A, Deane CS, Brook MS, Wilkinson DJ, Phillips BE, Philp A, Tarum J, Kadi F, Andersen D, Garcia AM, Smith K, Gallagher IJ, Szewczyk NJ, Cleasby ME, Atherton PJ (2020) Overexpression of the vitamin D receptor (VDR) induces skeletal muscle hypertrophy. Mol Metab 42:101059. https://doi.org/10.1016/j.molmet.2020.101059CrossRef

15.

Ceglia L, Niramitmahapanya S, da Silva MM, Rivas DA, Harris SS, Bischoff-Ferrari H, Fielding RA, Dawson-Hughes B (2013) A randomized study on the effect of vitamin D(3) supplementation on skeletal muscle morphology and vitamin D receptor concentration in older women. J Clin Endocrinol Metab 98:E1927–E1935. https://doi.org/10.1210/jc.2013-2820CrossRef

16.

Navarro-Valverde C, Sosa-Henriquez M, Alhambra-Exposito MR, Quesada-Gomez JM (2016) Vitamin D3 and calcidiol are not equipotent. J Steroid Biochem Mol Biol 164:205–208. https://doi.org/10.1016/j.jsbmb.2016.01.014CrossRef

17.

Perez-Castrillon JL, Duenas-Laita A, Brandi ML, Jodar E, Del Pino-Montes J, Quesada-Gomez JM, Cereto Castro F, Gomez-Alonso C, Gallego Lopez L, Olmos Martinez JM, Alhambra Exposito MR, Galarraga B, Gonzalez-Macias J, Bouillon R, Hernandez-Herrero G, Fernandez-Hernando N, Arranz-Gutierrez P, Chinchilla SP (2021) Calcifediol is superior to cholecalciferol in improving vitamin D status in postmenopausal women: a randomized trial. J Bone Miner Res. https://doi.org/10.1002/jbmr.4387CrossRef

18.

Bischoff-Ferrari HA, Dawson-Hughes B, Stocklin E, Sidelnikov E, Willett WC, Edel JO, Stahelin HB, Wolfram S, Jetter A, Schwager J, Henschkowski J, von Eckardstein A, Egli A (2012) Oral supplementation with 25(OH)D3 versus vitamin D3: effects on 25(OH)D levels, lower extremity function, blood pressure, and markers of innate immunity. J Bone Miner Res 27:160–169. https://doi.org/10.1002/jbmr.551CrossRef

19.

Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK, Durazo-Arvizu RA, Gallagher JC, Gallo RL, Jones G, Kovacs CS, Mayne ST, Rosen CJ, Shapses SA (2011) The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know (in eng). J Clin Endocrinol Metab 96:53–58. https://doi.org/10.1210/jc.2010-2704CrossRef

20.

Quack Lötscher KCIA D, Bischoff-Ferrari HA, Burckhardt P (2012) Vitamin-D deficiency: evidence, safety, and recommendations for the Swiss population. University of Zurich, Bern

21.

Meyer O, Dawson-Hughes B, Sidelnikov E, Egli A, Grob D, Staehelin HB, Theiler G, Kressig RW, Simmen HP, Theiler R, Bischoff-Ferrari HA (2015) Calcifediol versus vitamin D3 effects on gait speed and trunk sway in young postmenopausal women: a double-blind randomized controlled trial. Osteoporos Int 26:373–381. https://doi.org/10.1007/s00198-014-2949-1CrossRef

22.

Bischoff HA, Stahelin HB, Dick W, Akos R, Knecht M, Salis C, Nebiker M, Theiler R, Pfeifer M, Begerow B, Lew RA, Conzelmann M (2003) Effects of vitamin D and calcium supplementation on falls: a randomized controlled trial (in eng). J Bone Miner Res 18:343–351CrossRef

23.

Stoll T, Huber E, Seifert B, Michel BA, Stucki G (2000) Maximal isometric muscle strength: normative values and gender-specific relation to age. Clin Rheumatol 19:105–113. https://doi.org/10.1007/s100670050026CrossRef

24.

Podsiadlo D, Richardson S (1991) The timed “Up & Go”: a test of basic functional mobility for frail elderly persons. J Am Geriatr Soc 39:142–148. https://doi.org/10.1111/j.1532-5415.1991.tb01616.xCrossRef

25.

Wolf AM, Hunter DJ, Colditz GA, Manson JE, Stampfer MJ, Corsano KA, Rosner B, Kriska A, Willett WC (1994) Reproducibility and validity of a self-administered physical activity questionnaire. Int J Epidemiol 23:991–999. https://doi.org/10.1093/ije/23.5.991CrossRef

26.

Walker DK, Fry CS, Drummond MJ, Dickinson JM, Timmerman KL, Gundermann DM, Jennings K, Volpi E, Rasmussen BB (2012) PAX7+ satellite cells in young and older adults following resistance exercise. Muscle Nerve 46:51–59. https://doi.org/10.1002/mus.23266CrossRef

27.

Srikuea R, Zhang X, Park-Sarge OK, Esser KA (2012) VDR and CYP27B1 are expressed in C2C12 cells and regenerating skeletal muscle: potential role in suppression of myoblast proliferation (in Eng). Am J Physiol Cell Physiol. https://doi.org/10.1152/ajpcell.00014.2012CrossRef

28.

Weller MG (2016) Quality issues of research antibodies. Anal Chem Insights 11:21–27. https://doi.org/10.4137/ACI.S31614CrossRef

29.

Pike JW (2016) Closing in on vitamin D action in skeletal muscle: early activity in muscle stem cells? Endocrinology 157:48–51. https://doi.org/10.1210/en.2015-2009CrossRef

30.

Brooke MH, Kaiser KK (1970) Muscle fiber types: how many and what kind? (in eng). Arch Neurol 23:369–379CrossRef

31.

Boersma D, Demontiero O, Mohtasham Amiri Z, Hassan S, Suarez H, Geisinger D, Suriyaarachchi P, Sharma A, Duque G (2012) Vitamin D status in relation to postural stability in the elderly. J Nutr Health Aging 16:270–275. https://doi.org/10.1007/s12603-011-0345-5CrossRef

32.

Pfeifer M, Begerow B, Minne HW, Abrams C, Nachtigall D, Hansen C (2000) Effects of a short-term vitamin D and calcium supplementation on body sway and secondary hyperparathyroidism in elderly women (in eng). J Bone Miner Res 15:1113–1118CrossRef

33.

Pfeifer M, Begerow B, Minne HW, Suppan K, Fahrleitner-Pammer A, Dobnig H (2008) Effects of a long-term vitamin D and calcium supplementation on falls and parameters of muscle function in community-dwelling older individuals (in Eng). Osteoporos Int. https://doi.org/10.1007/s00198-008-0662-7CrossRef

34.

Eriksen SS-LJ, HirataPedersenGraven-Nielsen RPKKT, Vestergaard P (2019) Effects of vitamin D supplementaiton on well-being, postural control, muscle strength, bone and calcitropic hormones—a randomized double blind placebo controlled trial. J Aging Res Clin Practice 8:49–56

35.

Vaes AMM, Tieland M, Toussaint N, Nilwik R, Verdijk LB, van Loon LJC, de Groot L (2018) Cholecalciferol or 25-hydroxycholecalciferol supplementation does not affect muscle strength and physical performance in prefrail and frail older adults. J Nutr 148:712–720. https://doi.org/10.1093/jn/nxy024CrossRef

36.

Bislev LS, Grove-Laugesen D, Rejnmark L (2021) Vitamin D and muscle health: a systematic review and meta-analysis of randomized placebo-controlled trials. J Bone Miner Res 36:1651–1660. https://doi.org/10.1002/jbmr.4412CrossRef

37.

Yoshikawa S, Nakamura T, Tanabe H, Imamura T (1979) Osteomalacic myopathy (in eng). Endocrinol Jpn 26:65–72CrossRef

38.

Palmucci L, Bertolotto A, Doriguzzi C, Mongini T, Coda R (1982) Osteomalacic myopathy in a case of diffuse nodular lipomatosis of the small bowel (in eng). Acta Neurol Belg 82:65–71

39.

Sorensen OH, Lund B, Saltin B, Lund B, Andersen RB, Hjorth L, Melsen F, Mosekilde L (1979) Myopathy in bone loss of ageing: improvement by treatment with 1 alpha-hydroxycholecalciferol and calcium (in eng). Clin Sci (Lond) 56:157–161CrossRef

40.

Hayes A, Rybalka E, Debruin DA, Hanson ED, Scott D, Sanders K (2019) The effect of yearly-dose vitamin D supplementation on muscle function in mice. Nutrients. https://doi.org/10.3390/nu11051097CrossRef

41.

Sanders KM, Stuart AL, Williamson EJ, Simpson JA, Kotowicz MA, Young D, Nicholson GC (2010) Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial (in eng). JAMA 303:1815–1822. https://doi.org/10.1001/jama.2010.594CrossRef

42.

Smith H, Anderson F, Raphael H, Maslin P, Crozier S, Cooper C (2007) Effect of annual intramuscular vitamin D on fracture risk in elderly men and women—a population-based, randomized, double-blind, placebo-controlled trial. Rheumatology (Oxford) 46:1852–1857. https://doi.org/10.1093/rheumatology/kem240CrossRef

43.

Bischoff-Ferrari HA, Dawson-Hughes B, Orav EJ, Staehelin HB, Meyer OW, Theiler R, Dick W, Willett WC, Egli A (2016) Monthly high-dose vitamin D treatment for the prevention of functional decline: a randomized clinical trial. JAMA Intern Med 176:175–183. https://doi.org/10.1001/jamainternmed.2015.7148CrossRef

44.

Dawson-Hughes B, Wang J, Barger K, Bischoff-Ferrari HA, Sempos CT, Durazo-Arvizu RA, Ceglia L (2022) Intra-trial mean 25(OH)D and PTH levels and risk of falling in older men and women in the Boston STOP IT trial. J Clin Endocrinol Metab. https://doi.org/10.1210/clinem/dgac012CrossRef

45.

Zittermann A, Berthold HK, Pilz S (2021) The effect of vitamin D on fibroblast growth factor 23: a systematic review and meta-analysis of randomized controlled trials. Eur J Clin Nutr 75:980–987. https://doi.org/10.1038/s41430-020-00725-0CrossRef

46.

Burnett-Bowie SA, Leder BZ, Henao MP, Baldwin CM, Hayden DL, Finkelstein JS (2012) Randomized trial assessing the effects of ergocalciferol administration on circulating FGF23. Clin J Am Soc Nephrol 7:624–631. https://doi.org/10.2215/CJN.10030911CrossRef

47.

Beckman MJ, Johnson JA, Goff JP, Reinhardt TA, Beitz DC, Horst RL (1995) The role of dietary calcium in the physiology of vitamin D toxicity: excess dietary vitamin D3 blunts parathyroid hormone induction of kidney 1-hydroxylase. Arch Biochem Biophys 319:535–539. https://doi.org/10.1006/abbi.1995.1328CrossRef

Title: Effect of vitamin D3 vs. calcifediol on VDR concentration and fiber size in skeletal muscle
Authors: Lisa Ceglia
Donato A. Rivas
Mathias Schlögl
Grace B. Fielding
Andreas Egli
Heike A. Bischoff-Ferrari
Bess Dawson-Hughes
Publication date: 16-11-2022
Publisher: Springer Nature Singapore
Published in: Journal of Bone and Mineral Metabolism / Issue 1/2023
Print ISSN: 0914-8779
Electronic ISSN: 1435-5604
DOI: https://doi.org/10.1007/s00774-022-01374-y

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