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Vitamin D receptors get worse with age with osteoporosis – Dec 2018

Vitamin D Receptor in Muscle Atrophy of Elderly Patients: A Key Element of Osteoporosis-Sarcopenia Connection

Aging Dis. 2018 Dec; 9(6): 952–964, doi: 10.14336/AD.2018.0215
Manuel Scimeca,1,2 Federica Centofanti,1 Monica Celi,3 Elena Gasbarra,3 Giuseppe Novelli,1,4 Annalisa Botta,1, and Umberto Tarantino3,5,*

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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.


DISCUSSIONS

It is known that Vitamin D plays an essential role in skeletal muscle homeostasis, but its precise physiological function and relevance to normal muscle physiology is not well understood [17]. In this context, Bischoff-Ferrari et al. reported the expression of VDR in muscle tissues demonstrating that older age was significantly associated with decreased VDR expression, independent of biopsy location and serum 25(OH)D levels [18]. Starting from these evidences, in this study we investigated the relationship among muscle quality, evaluated in term of percentage of atrophic fibers, VDR nuclear expression and the main VDR polymorphisms associated with OP or OA namely Cdx2, TaqI and FokI. To this end, we collected biopsies of vastus lateralis from 99 patients who underwent hip surgery: 44 OP patients and 55 OA patients. Morphometrical examination showed a delay of the onset of sarcopenia in OA patients respect to OP. This data is also supported by the consistent storage of Pax7 positive satellite cells that we found in muscle tissue of OA patients. Satellite cells play an indispensable role in muscle regeneration. The self-renewing proliferation of these cells not only maintains the stem cell population but also provides numerous myogenic cells, which proliferate, differentiate, fuse, and lead to new myofiber formation and reconstitution of a functional contractile apparatus [36]. The loss of satellite cells, and/or their degeneration, could reflect the alteration of muscle metabolism that occurs in patients affect by osteoporosis.
In this context, we recently showed that muscle tissues from OP patients were characterized by the imbalance between myostatin and bone morphogenetics proteins (BMPs) pathways [37,38,39,40]. VDR was evaluated both at cytoplasmic and nuclear level by immune- histochemistry. Our results revealed a higher number of VDR positive nuclei in OA patients respect to OP. Conversely, no significant difference was observed respect to VDR cytoplasmic expression. It is important to note that these differences are not influenced by the serum level of 25(OH)D. Indeed, both our experimental groups were characterized by a condition of hypovitaminosis with very similar mean values of 25(OH)D serum concentration. On note, OA group was characterized by patients with a wide range of 25(OH)D values (min 4,20 - max 32,40 ng/ml).
In line with the results of Bischoff-Ferrari et al., we observed a general decrease of VDR positive myonuclei with the age considering both OA and OP patients. Noteworthy, analyzing the experimental groups individually, 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. Indeed, Braga et al. demonstrated that the activation of VDR in satellite cells induce the expression of known markers of muscle regeneration such as MyoD, myogenin, insuline-like growth factor-1 (IGF-1) and BMPs [40]. These evidences are also supported by our recent studies in which we demonstrated the high expression of BMP-2/4/7 and myogenin in muscle tissues of OA patients.
In order to better elucidate the role of VDR on muscle homeostasis and therefore explain the different pattern of VDR activation in OA and OP patients, we analyzed the Cdx2, TaqIand FokIVDR polymorphisms. The genotype distribution of the Cdx2 polymorphism showed a significant difference between OP and OA groups. In particular, we observed a higher frequency of A (35%) allele in the OA group compared to OP group (17%). Moreover, in OA patients we observed a significant increase of VDR positive myonuclei and the lower number of atrophic fiber compared to OP patients. No significant differences have been observed in genotype distribution of FokI and TaqI polymorphisms between OP and OA groups.
To investigate the influence of VDR polymorphisms on muscle quality, we studied the putative association between their genotypic distribution and the percentage of atrophic fibers in both OA and OP patients.
In this study, even if in a small sample size, we found that the G allele of Cdx2 polymorphism of VDR gene was significant associated with higher percentage of the atrophic type II fibers. The putative functional role of this allele is to decrease the binding activity of the Cdx2 protein on the VDR promoter thus reducing the transcription level of the VDR gene itself [25]. This finding suggests that the G allele could be responsible for the lower activation of VDR in satellite cells leading to reduced expression of gene implicated in muscle regeneration and consequent fiber atrophy in OA and OP groups. The second VDR polymorphism characterized is FokI, which is known to affect the translational start site of the VDR gene. OP and OA patients carrying the CT genotype showed more atrophic fibers compared to patients with CC genotype. These results are in line with literature data demonstrating that individuals with the T allele synthesize the full-length VDR protein (isoform T, 427 amino acids), while individuals with the C allele synthesize a slightly truncated version of the VDR protein (isoform C, 424 aminoacids). The truncated C isoform of the VDR proteins displays a higher transcriptional activation of reporter genes in vitro and interacts more efficiently with the key transcription factor TFIIB, than the longer T isoform [42]. It is important to note that both OA and OP patients with the combination of the GG/CT genotypes showed a significant increase in the number of type II atrophic fibers respect to the other VDR genotype combinations [2]. Another important aspect was the correlation between the number of VDR-positive myonuclei and VDR polymorphisms genotypes. We observed a significant correlation between the CC FokI genotype, which activates the VDR transcription, and the nuclear localization of the VDR protein. On the basis of this observation, it is possible to speculate that FokI polymorphism could also promote the translocation of the VDR protein from cytoplasm to cell nucleus. Further functional studies are needed to verify this novel hypothesis which could provide additional information about the role of VDR in muscle-skeletal pathway. To the best of our knowledge, this is the first report demonstrating this association, however, given the small sample size, genotyping of these SNPs is recommended to be carried out in different populations with more samples. Overall, our data highlight the prominence of VDR activity and genetic variability on muscle aging and sarcopenia typical of OA and OP patients.

Conclusions

In the era of personalized medicine, the identification of molecules/genes involved in aging of musculoskeletal apparatus represent one of the most important scientific research fields.
In this context, here we showed as the activation of VDR (nuclear translocation) is strictly associated with the percentage of atrophic muscle fibers. These preliminary evidences, if confirmed in larger cohort of samples, will provide new insights in the pathogenesis and age-related muscle disorders based on the genotyping of the VDR gene.

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