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Aging and disease    2018, Vol. 9 Issue (6) : 952-964     DOI: 10.14336/AD.2018.0215
Orginal Article |
Vitamin D Receptor in Muscle Atrophy of Elderly Patients: A Key Element of Osteoporosis-Sarcopenia Connection
Scimeca Manuel1,2, Centofanti Federica1, Celi Monica3, Gasbarra Elena3, Novelli Giuseppe1,4, Botta Annalisa1, Tarantino Umberto3,5,*
1Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, Via Montpellier 1, Rome 00133, Italy.
2IRCCS San Raffaele, 00166, Rome, Italy.
3Department of Orthopedics and Traumatology, "Tor Vergata" University of Rome, "Policlinico Tor Vergata" Foundation, Rome, Italy.
4Neuromed IRCCS, Pozzilli (IS), Italy.
5Department of Experimental Medicine and Surgery, University “Tor Vergata”, Rome 00133, Italy.
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Abstract  

In this study, we investigated the relationship between sarcopenia (evaluated in term of fibers atrophy), vitamin d receptor protein expression and TaqI/Cdx2/FokI VDR genotypes in an Italian cohort of osteoporosis(n=44) and osteoarthritis (n=55) patients. Muscle biopsies were fixed and investigated by both immunohistochemistry (vitamin d receptor expression) and transmission electron microscopy (satellite stem cells niches). Vitamin d receptor polymorphisms were studied on DNA extracted from muscle paraffin sections. For the first time, we reported that aging differently affects the VDR activation in OA and OP patients. In particular, while in OP patients we observed a significant reduction of VDR positive myonuclei with age, no “age effect” was observed in OA patients. The frequent activation of VDR could explain the lower number of atrophic fiber that we observed in OA patients respect to OP. From genetic point of view, we showed a putative association among polymorphisms FokI and Cdx2 of VDR gene, vitamin d receptor activation and the occurrence of sarcopenia. Altogether these data open new prospective for the prevention and cure of age-related muscle disorders.

Keywords Vitamin d receptor      polymorphisms      sarcopenia      osteoporosis      osteoarthritis      aging     
Corresponding Authors: Tarantino Umberto   
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These authors contributed equally to this work

Issue Date: 12 November 2017
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Scimeca Manuel
Centofanti Federica
Celi Monica
Gasbarra Elena
Novelli Giuseppe
Botta Annalisa
Tarantino Umberto
Cite this article:   
Scimeca Manuel,Centofanti Federica,Celi Monica, et al. Vitamin D Receptor in Muscle Atrophy of Elderly Patients: A Key Element of Osteoporosis-Sarcopenia Connection[J]. Aging and disease, 2018, 9(6): 952-964.
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http://www.aginganddisease.org/EN/10.14336/AD.2018.0215     OR     http://www.aginganddisease.org/EN/Y2018/V9/I6/952
AntibodyDilutionRetrievalClone
Slow-myosin1:100EDTA citrate pH 7.8NOQ7.5.4D, Abcam
Fast-myosin1:100EDTA citrate pH 8.0MY-32, Abcam
PAX-71:200Citrate pH 6.0ab55494, Abcam
VDR1:100Citrate pH 6.02F4, Novus Biologicals
Table 1  List of primary antibodies.
Figure 1.  Vitamin D serum level and muscle quality. (A) Graph shows mean value of vitamin D serum concentration in OA e OP patients. (B) Graph displays the percentage of atrophic fibers in OA patients. (C) Graph displays the percentage of atrophic fibers in OP patients. (D) Graph shows higher number of Pax7 positive satellite cells in OA as compared OP patients. (E) Representative image of anti-Pax7 immunoreaction of a muscle biopsies of an OA patient (scale bar represents 50µm). Arrows indicate several Pax7 positive myonuclei. (F) Representative image of anti-Pax7 immunoreaction of a muscle biopsies of an OP patient (scale bar represents 50µm) Arrow indicates a Pax7 positive cell. (G) Electron micrograph displays a well conserved satellite cell (arrow) net to myonucleus (asterisk) in a muscle biopsy of an OA patient (scale bar represents 2µm). H) Electron micrograph shows a satellite cells in degeneration (arrow) next to myonucleus (asterisk) in a muscle biopsy of an OP patient (scale bar represents 2µm).
OAOP

Age74.42±1,2570.90±1,46

Body Mass Index25.84 ± 0.8523.33 ± 3.21

T score L1-L4-1.4 ± 1.12-2.4 ± 1.08

Femoral neck T score-1.2 ± 0.99-2.99 ± 1.12

Kellgren-Lawrence grade3-41-2

25(OH)D (ng/ml)16.90±2,7510.12±1,41
Table 2  Baseline characteristics of AO and OP patients.
Figure 2.  VDR expression in muscle biopsies of OA and OP patients. (A) Representative image of anti-VDR immunoreaction of a muscle biopsies of an AO patient (scale bar represents 50µm). Arrows indicate numerous VDR positive myonuclei. (B) Representative image of anti-VDR immunoreaction of a muscle biopsies of an OP patient (scale bar represents 50µm). Arrows indicate rare VDR positive myonuclei. (C) Graph shows higher number of VDR positive myonuclei in OA patients as compared to OP. (D) There is no significant difference between cytoplasmic expression of VDR in OA and OP patients. (E) Graph displays correlation between VDR nuclear expression and the age of the patients. (F) Graph shows correlation between VDR nuclear expression and the age of OA patients. Graph displays correlation between VDR nuclear expression and the age of OP patients.
Figure 3.  Genotypes distribution of the Cdx2, FokI and TaqI polymorphisms between OP and OA groups. (A) Fisher’s Exact test analysis (online VassarStats Statistical Software) showed a significant difference in genotype distribution for Cdx2 polymorphism between the OP and OA groups (p= 0.002). (B, C) There was not a significant difference in in genotype distribution for FokI and TaqI (0.50 and 0.48 respectively) polymorphisms in OP and OA patients (B-C). P-value was calculated using Fisher Exact Probability Test for a two-rows by three-columns contingency table (p< 0.05).
Table 3  Genotypes and Alleles frequencies of VDR Gene Polymorphisms in OP and OA patients. Deviations from Hardy-Weinberg equilibrium for the three SNPs were not observed for all three SNPs: Cdx2, FokI and TaqI (p > 0.05).
Figure 4.  Comparison between FokI, Cdx2 and TaqI polymorphisms and the number of positive myonuclei. (A) The comparison between FokI polymorphism and the number of positive myonuclei showed a significant difference in patients with CC genotype respect to patients with CT genotype (p=0.0044). (B) No significant difference in the nuclear expression of VDR was observed in Cdx2. (C) No significant difference in the nuclear expression of VDR was observed in TaqI.
Figure 5.  Comparison between FokI, Cdx2 and TaqI polymorphisms and the percentage of positive myonuclei. (A) The comparison between Cdx2 genotypes and muscle atrophy displays a significant group effect (GG =50%; GA= 38%; AA=18%; p=0,0004). Mann-Whitney test shows significant higher percentage of muscle atrophy (Type I = 17% vs Type II = 33%) in patients with GG genotype respect to patients with GA genotype (Type I = 17% vs Type II = 19%) (p=0,0035) and in patients with GA (Type I = 17% vs Type II = 19%) respect to patients with AA (Type I = 5% vs Type II = 13%) genotypes (p=0.0004). (B) The comparison between genotypes of FokI polymorphisms and muscle atrophy (CC =38%; CT= 45%; TT=46%) did not show a significant group effect (p=0,1080). Mann-Whitney test shows significant higher percentage of muscle atrophy in patients with CT genotype (Type I = 17% vs Type II = 28%) compared to patients with CC genotype (Type I = 17% vs Type II = 20%) (p= 0,0440). (C) The comparison between genotypes of TaqI polymorphisms and muscle atrophy (TT=50%; TC= 40%; CC=37%) did not reveal a significant group effect (p=0,1282). (D) Patients with GG/CT and GG/CC genotypes showed a significant higher percentage of type II atrophic fibers (Type II =35% and 25% respectively) respect to other genotypes combination (Type I =18% and 15% respectively).
[1] Tarantino U, Piccirilli E, Fantini M, et al. (2015). Sarcopenia and fragility fractures: molecular and clinical evidence of the bone-muscle interaction. J Bone Joint Surg Am, 97(5):429–37.
[2] Tarantino U, Baldi J, Celi M, et al. (2013). Osteoporosis and sarcopenia: the connections. Aging Clin Exp Res, 25 Suppl 1: S93–5.
[3] Bonaldo P, Sandri M (2013). Cellular and molecular mechanisms of muscle atrophy. Dis Model Mech, 6(1):25–39.
[4] Narici MV, Maffulli N (2010). Sarcopenia: characteristics, mechanisms and functional significance. Br Med Bull, 95:139–159.
[5] Ferraro E, Pin F, Gorini S, et al. (2016). Improvement of skeletal muscle performance in ageing by the metabolic modulator Trimetazidine. J Cachexia Sarcopenia Muscle, 7(4):449–57.
[6] Brotto M, Johnson ML (2014). Endocrine crosstalk between muscle and bone Curr Osteoporos Rep, 12(2):135–41.
[7] Sartori R, Sandri M (2015). BMPs and the muscle-bone connection. Bone, 80:37–42.
[8] Gunton JE, Girgis CM, Baldock PA, et al. (2015). Bone muscle interactions and vitamin D. Bone, 80:89–94.
[9] Sanders KM, Scott D, Ebeling PR (2014). Vitamin D deficiency and its role in muscle-bone interactions in the elderly. Curr Osteoporos Rep, 12(1):74–81.
[10] Tanner SB, Harwell SA (2015). More than healthy bones: a review of vitamin D in muscle health. Ther Adv Musculoskelet Dis, 7(4):152–9.
[11] Resmini G, Tarantino U, Iolascon G (2013). Vitamin D: role and opportunity to prescribe. Aging Clin Exp Res, 25 Suppl 1: S125–7.
[12] Bruyère O, Cavalier E, Souberbielle JC, et al. (2014). Effects of vitamin D in the elderly population: current status and perspectives. Arch Public Health, 72(1):32.
[13] Boland RL (2011). VDR activation of intracellular signaling pathways in skeletal muscle. Mol Cell Endocrinol, 347:11–16.
[14] Abboud M, Puglisi DA, Davies BN, et al. (2013). Evidence for a specific uptake and retention mechanism for 25-hydroxyvitamin D (25OHD) in skeletal muscle cells. Endocrinology, 154:3022–3030.
[15] Tan LJ, Liu SL, Lei SF, et al. (2012). Molecular genetic studies of gene identification for sarcopenia. Hum Genet, 131(1):1–31.
[16] Endo I, Inoue D, Mitsui T, et al. (2003). Deletion of vitamin D receptor gene in mice results in abnormal skeletal muscle development with deregulated expression of myoregulatory transcription factors. Endocrinology, 144(12):5138–44.
[17] Ceglia L (2008). Vitamin D and skeletal muscle tissue and function. Mol Aspects Me., 29(6):407–14.
[18] Bischoff-Ferrari HA, Borchers M, Gudat F, et al. (2004). Vitamin D receptor expression in human muscle tissue decreases with age. J Bone Miner Res, 19(2):265–9.
[19] Monticielo OA, Teixeira TDM, Chies JAB, et al. (2012). Vitamin D and polymorphisms of VDR gene in patients with systemic lupus erythematosus. Clin Rheumatol, 31: 1411–1421.
[20] Smolders J, Peelen E, Thewissen M, et al. (2009). The relevance of vitamin D receptor gene polymorphisms for vitamin D research in multiple sclerosis. Autoimmun Rev Elsevier BV, 8: 621–626.
[21] Whitfield GK, Remus LS, Jurutka PW, et al. (2001). Functionally relevant polymorphisms in the human nuclear vitamin D receptor gene. Mol Cell Endocrinol, 177: 145–159.
[22] Bahat G, Saka B, Erten N, et al. (2010). BsmI polymorphism in the vitamin D receptor gene is associated with leg extensor muscle strength in elderly men. Aging Clin Exp Res, 22(3):198–205.
[23] Walsh S, Ludlow AT, Metter EJ, et al. (2016). Replication study of the vitamin D receptor (VDR) genotype association with skeletal muscle traits and sarcopenia. Aging Clin Exp Res, 28(3):435–42.
[24] Roth SM, Zmuda JM, Cauley JA, et al. (2004). Vitamin D receptor genotype is associated with fat-free mass and sarcopenia in elderly men. J Gerontol A Biol Sci Med Sci, 59(1):10–5.
[25] Arai H, Miyamoto KI, Yoshida M, et al. (2001). The polymorphism in the caudal-related homeodomain protein Cdx-2 binding element in the human vitamin D receptor gene. J Bone Miner Res, 16(7):1256–64.
[26] Uitterlinden AG, Ralston SH, Brandi ML, et al. (2006). The association between common vitamin D receptor gene variations and osteoporosis: a participant-level meta-analysis. Ann Intern Med, 145(4):255–64.
[27] Fang Y, van Meurs JB, Bergink AP, et al. (2003). Cdx-2 polymorphism in the promoter region of the human vitamin D receptor gene determines susceptibility to fracture in the elderly. J Bone Miner Res, 18(9):1632–41.
[28] Zhang ZL, He JW, Qin YJ, et al. (2006). Association of bone metabolism related genes polymorphisms with the effect of raloxifene hydrochloride on bone mineral density and bone turnover markers in postmenopausal women with osteoporosis. Zhonghua Yi Xue Yi Chuan Xue Za Zhi, 23(2):129–33.
[29] Ling Y, Lin H, Aleteng Q, et al. (2016). Cdx-2 polymorphism in Vitamin D Receptor gene was associated with serum 25-hydroxyvitamin D levels, bone mineral density and fracture in middle-aged and elderly Chinese women. Mol Cell Endocrinol, 427:155–61.
[30] Casado-Díaz A, Cuenca-Acevedo R, Navarro-Valverde C, et al. (2013). Vitamin D status and the Cdx-2 polymorphism of the vitamin D receptor gene are determining factors of bone mineral density in young healthy postmenopausal women. J Steroid Biochem Mol Biol, 136:187–9.
[31] Celi M, Rao C, Scialdoni A, et al. (2013). Bone mineral density evaluation in osteoporosis: why yes and why not? Aging Clin Exp Res, 25 Suppl 1 S47-9.
[32] Piccirilli E, Gasbarra E, Baldi J, et al. (2014). Can muscular impairment be the ‘‘key’’ for femoral fracture? J Gerontol Geriatr Res, 3: 183.
[33] Kellgren JH, Lawrence JS (1957). Radiological assessment of osteoarthrosis. Ann Rheum Dis, 16(2):494–502.
[34] Majer EJ, Iatridis JC, Chan Det al. (2013). Genetic polymorphisms associated with intervertebral disc degeneration. Spine J, 13(3):299–317.
[35] Colombini A, Cauci S, Lombardi Get al. (2013). Relationship between vitamin D receptor gene (VDR). J. Steroid Biochem. Mol Biol, 138: 24–40.
[36] Yin H, Price F, Rudnicki MA (2013). Satellite cells and the muscle stem cell niche. Physiol Rev., 93(1):23–67.
[37] Scimeca M, Piccirilli E, Mastrangeli F, et al. (2017). Bone Morphogenetic Proteins and myostatin pathways: key mediator of human sarcopenia. J Transl Med, 15(1):34.
[38] Tarantino U, Scimeca M, Piccirilli E, al. (2015). Sarcopenia: a histological and immunohistochemical study on age-related muscle impairment. Aging Clin Exp Res, Suppl 1: S51–60.
[39] Scimeca M, Bonanno E, Piccirilli E, et al. (2015). Satellite Cells CD44 Positive Drive Muscle Regeneration in Osteoarthritis Patients. Stem Cells Int, 469459.
[40] Tarantino U, Baldi J, Scimeca M, et al. (2016). The role of sarcopenia with and without fracture. Injury, Suppl 4: S3–S10.
[41] Braga M, Simmons Z, Norris KC, et al. (2017). Vitamin D induces myogenic differentiation in skeletal muscle derived stem cells. Endocr Connect, 6(3):139–150.
[42] Roth SM, Zmuda JM, Cauley JAet al. (2004). Vitamin D receptor genotype is associated with fat-free mass and sarcopenia in elderly men. J Gerontol A Biol Sci Med Sci, 59(1):10–5.
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