Influence of Vitamin D on Sarcopenia Pathophysiology: A Longitudinal Study in Humans and Basic Research in Knockout Mice

Overview

Journal J Cachexia Sarcopenia Muscle

Date 2022 Oct 14

PMID 36237134

Authors

Takafumi Mizuno

Tohru Hosoyama

Makiko Tomida

Yoko Yamamoto

Yuko Nakamichi

Shigeaki Kato

Minako Kawai-Takaishi

Shinya Ishizuka

Yukiko Nishita

Chikako Tange

Hiroshi Shimokata

Shiro Imagama

Rei Otsuka

Affiliations

Soon will be listed here.

Abstract

Background: Vitamin D is an essential nutrient in musculoskeletal function; however, its relationship to sarcopenia remains ambiguous, and the mechanisms and targets of vitamin D activity have not been elucidated. This study aimed to clarify the role of vitamin D in mature skeletal muscle and its relationship with sarcopenia.

Methods: This epidemiological study included 1653 community residents who participated in both the fifth and seventh waves of the National Institute for Longevity Sciences, Longitudinal Study of Aging and had complete background data. Participants were classified into two groups: vitamin D-deficient (serum 25-hydroxyvitamin D < 20 ng/mL) and non-deficient (serum 25-hydroxyvitamin D ≥ 20 ng/mL); they underwent propensity-score matching for background factors (age, sex, height, weight, comorbidities, smoker, alcohol intake, energy intake, vitamin D intake, steps, activity, season and sarcopenia). Changes in muscle strength and mass over the 4-year period were compared. For basic analysis, we generated Myf6 Vitamin D Receptor (VDR)-floxed (Vdr ) mice with mature muscle fibre-specific vitamin D receptor knockout, injected tamoxifen into 8-week-old mice and analysed various phenotypes at 16 weeks of age.

Results: Grip strength reduction was significantly greater in the deficient group (-1.55 ± 2.47 kg) than in the non-deficient group (-1.13 ± 2.47 kg; P = 0.019). Appendicular skeletal muscle mass reduction did not differ significantly between deficient (-0.05 ± 0.79 kg) and non-deficient (-0.01 ± 0.74 kg) groups (P = 0.423). The incidence of new cases of sarcopenia was significantly higher in the deficient group (15 vs. 5 cases; P = 0.039). Skeletal muscle phenotyping of Vdr mice showed no significant differences in muscle weight, myofibre percentage or myofibre cross-sectional area; however, both forelimb and four-limb muscle strength were significantly lower in Vdr mice (males: forelimb, P = 0.048; four-limb, P = 0.029; females: forelimb, P < 0.001; four-limb, P < 0.001). Expression profiling revealed a significant decrease in expression of sarcoendoplasmic reticulum Ca -ATPase (SERCA) 1 (P = 0.019) and SERCA2a (P = 0.049) genes in the Vdr mice. In contrast, expression of non-muscle SERCA2b and myoregulin genes showed no changes.

Conclusions: Vitamin D deficiency affects muscle strength and may contribute to the onset of sarcopenia. Vitamin D-VDR signalling has minimal influence on the regulation of muscle mass in mature myofibres but has a significant influence on muscle strength.

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References

Bischoff-Ferrari H, Borchers M, Gudat F, Durmuller U, Stahelin H, Dick W . Vitamin D receptor expression in human muscle tissue decreases with age. J Bone Miner Res. 2004; 19(2):265-9. DOI: 10.1359/jbmr.2004.19.2.265. View

Endo I, Inoue D, Mitsui T, Umaki Y, Akaike M, Yoshizawa T . Deletion of vitamin D receptor gene in mice results in abnormal skeletal muscle development with deregulated expression of myoregulatory transcription factors. Endocrinology. 2003; 144(12):5138-44. DOI: 10.1210/en.2003-0502. View

von Haehling S, Coats A, Anker S . Ethical guidelines for publishing in the Journal of Cachexia, Sarcopenia and Muscle: update 2021. J Cachexia Sarcopenia Muscle. 2021; 12(6):2259-2261. PMC: 8718061. DOI: 10.1002/jcsm.12899. View

Cruz-Jentoft A, Bahat G, Bauer J, Boirie Y, Bruyere O, Cederholm T . Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing. 2018; 48(1):16-31. PMC: 6322506. DOI: 10.1093/ageing/afy169. View

Brack A, Conboy M, Roy S, Lee M, Kuo C, Keller C . Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. Science. 2007; 317(5839):807-10. DOI: 10.1126/science.1144090. View

Mizuno T, Matsui Y, Tomida M, Suzuki Y, Nishita Y, Tange C . Differences in the mass and quality of the quadriceps with age and sex and their relationships with knee extension strength. J Cachexia Sarcopenia Muscle. 2021; 12(4):900-912. PMC: 8350198. DOI: 10.1002/jcsm.12715. View

Mithal A, Wahl D, Bonjour J, Burckhardt P, Dawson-Hughes B, Eisman J . Global vitamin D status and determinants of hypovitaminosis D. Osteoporos Int. 2009; 20(11):1807-20. DOI: 10.1007/s00198-009-0954-6. View

Kim B, Kwak M, Lee S, Koh J . Lack of Association Between Vitamin D and Hand Grip Strength in Asians: A Nationwide Population-Based Study. Calcif Tissue Int. 2018; 104(2):152-159. DOI: 10.1007/s00223-018-0480-7. View

Yoshizawa T, Handa Y, Uematsu Y, Takeda S, Sekine K, Yoshihara Y . Mice lacking the vitamin D receptor exhibit impaired bone formation, uterine hypoplasia and growth retardation after weaning. Nat Genet. 1997; 16(4):391-6. DOI: 10.1038/ng0897-391. View

10.

Bischoff-Ferrari H, Dietrich T, Orav E, Hu F, Zhang Y, Karlson E . Higher 25-hydroxyvitamin D concentrations are associated with better lower-extremity function in both active and inactive persons aged > or =60 y. Am J Clin Nutr. 2004; 80(3):752-8. DOI: 10.1093/ajcn/80.3.752. View

11.

Bischoff-Ferrari H, Dawson-Hughes B, Staehelin H, Orav J, Stuck A, Theiler R . Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials. BMJ. 2009; 339:b3692. PMC: 2755728. DOI: 10.1136/bmj.b3692. View

12.

RODMAN J, Baker T . Changes in the kinetics of muscle contraction in vitamin D-depleted rats. Kidney Int. 1978; 13(3):189-93. DOI: 10.1038/ki.1978.28. View

13.

Chen L, Woo J, Assantachai P, Auyeung T, Chou M, Iijima K . Asian Working Group for Sarcopenia: 2019 Consensus Update on Sarcopenia Diagnosis and Treatment. J Am Med Dir Assoc. 2020; 21(3):300-307.e2. DOI: 10.1016/j.jamda.2019.12.012. View

14.

Suzuki T, Kwon J, Kim H, Shimada H, Yoshida Y, Iwasa H . Low serum 25-hydroxyvitamin D levels associated with falls among Japanese community-dwelling elderly. J Bone Miner Res. 2008; 23(8):1309-17. DOI: 10.1359/jbmr.080328. View

15.

Haussler M, Jurutka P, Mizwicki M, Norman A . Vitamin D receptor (VDR)-mediated actions of 1α,25(OH)₂vitamin D₃: genomic and non-genomic mechanisms. Best Pract Res Clin Endocrinol Metab. 2011; 25(4):543-59. DOI: 10.1016/j.beem.2011.05.010. View

16.

Ceglia L, Niramitmahapanya S, Da Silva Morais M, Rivas D, Harris S, Bischoff-Ferrari H . A randomized study on the effect of vitamin D₃ supplementation on skeletal muscle morphology and vitamin D receptor concentration in older women. J Clin Endocrinol Metab. 2013; 98(12):E1927-35. PMC: 3849671. DOI: 10.1210/jc.2013-2820. View

17.

Metter E, Conwit R, Metter B, Pacheco T, Tobin J . The relationship of peripheral motor nerve conduction velocity to age-associated loss of grip strength. Aging (Milano). 1999; 10(6):471-8. DOI: 10.1007/BF03340161. View

18.

Girgis C, Clifton-Bligh R, Hamrick M, Holick M, Gunton J . The roles of vitamin D in skeletal muscle: form, function, and metabolism. Endocr Rev. 2012; 34(1):33-83. DOI: 10.1210/er.2012-1012. View

19.

Larsson L, Li X, Frontera W . Effects of aging on shortening velocity and myosin isoform composition in single human skeletal muscle cells. Am J Physiol. 1997; 272(2 Pt 1):C638-49. DOI: 10.1152/ajpcell.1997.272.2.C638. View

20.

Connelly D, Rice C, ROOS M, Vandervoort A . Motor unit firing rates and contractile properties in tibialis anterior of young and old men. J Appl Physiol (1985). 1999; 87(2):843-52. DOI: 10.1152/jappl.1999.87.2.843. View