VDR Regulates Simulated Microgravity-induced Atrophy in C2C12 Myotubes

Overview

Journal Sci Rep

Specialty Science

Date 2022 Jan 27

PMID 35082348

Authors

Ryo Yuzawa

Hiroyuki Koike

Ichiro Manabe

Yumiko Oishi

Affiliations

Soon will be listed here.

Abstract

Muscle wasting is a major problem leading to reduced quality of life and higher risks of mortality and various diseases. Muscle atrophy is caused by multiple conditions in which protein degradation exceeds its synthesis, including disuse, malnutrition, and microgravity. While Vitamin D receptor (VDR) is well known to regulate calcium and phosphate metabolism to maintain bone, recent studies have shown that VDR also plays roles in skeletal muscle development and homeostasis. Moreover, its expression is upregulated in muscle undergoing atrophy as well as after muscle injury. Here we show that VDR regulates simulated microgravity-induced atrophy in C2C12 myotubes in vitro. After 8 h of microgravity simulated using 3D-clinorotation, the VDR-binding motif was associated with chromatin regions closed by the simulated microgravity and enhancer regions inactivated by it, which suggests VDR mediates repression of enhancers. In addition, VDR was induced and translocated into the nuclei in response to simulated microgravity. VDR-deficient C2C12 myotubes showed resistance to simulated microgravity-induced atrophy and reduced induction of FBXO32, an atrophy-associated ubiquitin ligase. These results demonstrate that VDR contributes to the regulation of simulated microgravity-induced atrophy at least in part by controlling expression of atrophy-related genes.

Citing Articles

Vitamin D Supplementation Effects on Markers Related with Endothelial Function and Coagulation in Obese Orthopedic Patients: Insights from Acute and Chronic Cases.

Gawryjolek M, Wicinski M, Michalska Gawryjolek M, Zabrzynski J Nutrients. 2025; 17(5).

PMID: 40077751 PMC: 11902029. DOI: 10.3390/nu17050882.

Microgravity's effects on miRNA-mRNA regulatory networks in a mouse model of segmental bone defects.

Gautam A, Chakraborty N, Dimitrov G, Hoke A, Miller S, Swift K PLoS One. 2024; 19(12):e0313768.

PMID: 39621621 PMC: 11611151. DOI: 10.1371/journal.pone.0313768.

Differential effects of cholecalciferol and calcitriol on muscle proteolysis and oxidative stress in angiotensin II-induced C2C12 myotube atrophy.

Hirunsai M, Srikuea R Physiol Rep. 2024; 12(8):e16011.

PMID: 38627219 PMC: 11021198. DOI: 10.14814/phy2.16011.

Macrophage SREBP1 regulates skeletal muscle regeneration.

Oishi Y, Koike H, Kumagami N, Nakagawa Y, Araki M, Taketomi Y Front Immunol. 2024; 14:1251784.

PMID: 38259495 PMC: 10800357. DOI: 10.3389/fimmu.2023.1251784.

Striated Muscle Evaluation Based on Velocity and Amortization Ratio of Mechanical Impulse Propagation in Simulated Microgravity Environment.

Nistorescu A, Busnatu S, Dinculescu A, Olteanu G, Marin M, Jercalau C Biology (Basel). 2022; 11(11).

PMID: 36421391 PMC: 9687979. DOI: 10.3390/biology11111677.

References

Gomes M, Lecker S, Jagoe R, Navon A, GOLDBERG A . Atrogin-1, a muscle-specific F-box protein highly expressed during muscle atrophy. Proc Natl Acad Sci U S A. 2001; 98(25):14440-5. PMC: 64700. DOI: 10.1073/pnas.251541198. View

Girgis C, Mokbel N, Cha K, Houweling P, Abboud M, Fraser D . The vitamin D receptor (VDR) is expressed in skeletal muscle of male mice and modulates 25-hydroxyvitamin D (25OHD) uptake in myofibers. Endocrinology. 2014; 155(9):3227-37. PMC: 4207908. DOI: 10.1210/en.2014-1016. View

Sander J, Joung J . CRISPR-Cas systems for editing, regulating and targeting genomes. Nat Biotechnol. 2014; 32(4):347-55. PMC: 4022601. DOI: 10.1038/nbt.2842. View

Cadena S, Zhang Y, Fang J, Brachat S, Kuss P, Giorgetti E . Skeletal muscle in MuRF1 null mice is not spared in low-gravity conditions, indicating atrophy proceeds by unique mechanisms in space. Sci Rep. 2019; 9(1):9397. PMC: 6599046. DOI: 10.1038/s41598-019-45821-9. View

Hanai J, Cao P, Tanksale P, Imamura S, Koshimizu E, Zhao J . The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity. J Clin Invest. 2007; 117(12):3940-51. PMC: 2066198. DOI: 10.1172/JCI32741. View

Prufer K, Barsony J . Retinoid X receptor dominates the nuclear import and export of the unliganded vitamin D receptor. Mol Endocrinol. 2002; 16(8):1738-51. DOI: 10.1210/me.2001-0345. View

Heinz S, Benner C, Spann N, Bertolino E, Lin Y, Laslo P . Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol Cell. 2010; 38(4):576-89. PMC: 2898526. DOI: 10.1016/j.molcel.2010.05.004. View

Bodine S, Latres E, Baumhueter S, Lai V, Nunez L, Clarke B . Identification of ubiquitin ligases required for skeletal muscle atrophy. Science. 2001; 294(5547):1704-8. DOI: 10.1126/science.1065874. View

Girgis C, Cha K, Houweling P, Rao R, Mokbel N, Lin M . Vitamin D Receptor Ablation and Vitamin D Deficiency Result in Reduced Grip Strength, Altered Muscle Fibers, and Increased Myostatin in Mice. Calcif Tissue Int. 2015; 97(6):602-10. DOI: 10.1007/s00223-015-0054-x. View

10.

Makanae Y, Ogasawara R, Sato K, Takamura Y, Matsutani K, Kido K . Acute bout of resistance exercise increases vitamin D receptor protein expression in rat skeletal muscle. Exp Physiol. 2015; 100(10):1168-76. DOI: 10.1113/EP085207. View

11.

Fielitz J, Kim M, Shelton J, Latif S, Spencer J, Glass D . Myosin accumulation and striated muscle myopathy result from the loss of muscle RING finger 1 and 3. J Clin Invest. 2007; 117(9):2486-95. PMC: 1957544. DOI: 10.1172/JCI32827. View

12.

Sartori R, Romanello V, Sandri M . Mechanisms of muscle atrophy and hypertrophy: implications in health and disease. Nat Commun. 2021; 12(1):330. PMC: 7803748. DOI: 10.1038/s41467-020-20123-1. View

13.

Kim M, Fujiki R, Murayama A, Kitagawa H, Yamaoka K, Yamamoto Y . 1Alpha,25(OH)2D3-induced transrepression by vitamin D receptor through E-box-type elements in the human parathyroid hormone gene promoter. Mol Endocrinol. 2006; 21(2):334-42. DOI: 10.1210/me.2006-0231. View

14.

Christakos S, Dhawan P, Benn B, Porta A, Hediger M, Oh G . Vitamin D: molecular mechanism of action. Ann N Y Acad Sci. 2007; 1116:340-8. DOI: 10.1196/annals.1402.070. View

15.

Chen S, Villalta S, Agrawal D . FOXO1 Mediates Vitamin D Deficiency-Induced Insulin Resistance in Skeletal Muscle. J Bone Miner Res. 2015; 31(3):585-95. PMC: 4814301. DOI: 10.1002/jbmr.2729. View

16.

Calzia D, Ottaggio L, Cora A, Chiappori G, Cuccarolo P, Cappelli E . Characterization of C2C12 cells in simulated microgravity: Possible use for myoblast regeneration. J Cell Physiol. 2019; 235(4):3508-3518. DOI: 10.1002/jcp.29239. View

17.

Creyghton M, Cheng A, Welstead G, Kooistra T, Carey B, Steine E . Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc Natl Acad Sci U S A. 2010; 107(50):21931-6. PMC: 3003124. DOI: 10.1073/pnas.1016071107. View

18.

Furukawa T, Tanimoto K, Fukazawa T, Imura T, Kawahara Y, Yuge L . Simulated microgravity attenuates myogenic differentiation via epigenetic regulations. NPJ Microgravity. 2018; 4:11. PMC: 5966377. DOI: 10.1038/s41526-018-0045-0. View

19.

Carlberg C, Campbell M . Vitamin D receptor signaling mechanisms: integrated actions of a well-defined transcription factor. Steroids. 2012; 78(2):127-36. PMC: 4668715. DOI: 10.1016/j.steroids.2012.10.019. View

20.

Irazoqui A, Boland R, Buitrago C . Actions of 1,25(OH)2-vitamin D3 on the cellular cycle depend on VDR and p38 MAPK in skeletal muscle cells. J Mol Endocrinol. 2014; 53(3):331-43. DOI: 10.1530/JME-14-0102. View