{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T16:26:10Z","timestamp":1791044770362,"version":"4.1.0"},"reference-count":50,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2021,12,8]],"date-time":"2021-12-08T00:00:00Z","timestamp":1638921600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2022,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Vitamin D deficiency leads to pathologies of multiple organ systems including skeletal muscle. Patients with severe vitamin D deficiency exhibit muscle weakness and are susceptible to frequent falls. Mice lacking a functional vitamin D receptor (VDR) develop severe skeletal muscle atrophy immediately after weaning. But the root cause of myopathies when vitamin D signalling is impaired is unknown. Because vitamin D deficiency leads to metabolic changes as well, we hypothesized that the skeletal muscle atrophy in mice lacking VDR may have a metabolic origin.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We analysed wild\u2010type (WT) mice as well as vitamin D receptor null (vdr\u2212\/\u2212) mice for skeletal muscle proteostasis, energy metabolism, systemic glucose homeostasis, and muscle glycogen levels. Dysregulation of signalling pathways as well as the glycogen synthesis and utilization machinery were also analysed using western blots. qRT\u2013PCR assays were performed to understand changes in mRNA levels.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Skeletal muscles of vdr\u2212\/\u2212 exhibited higher expression levels of muscle\u2010specific E3 ubiquitin ligases and showed increased protein ubiquitination, suggesting up\u2010regulation of protein degradation. Foxo1 transcription factor was activated in vdr\u2212\/\u2212 while Foxo3 factor was unaffected. Fasting protein synthesis as well as mTORC1 pathways were severely down\u2010regulated in vdr\u2212\/\u2212 mice. Skeletal muscle ATP levels were low in vdr\u2212\/\u2212 (0.58\u00a0\u00b1\u00a00.18\u00a0\u03bcmol\/mL vs. 1.6\u00a0\u00b1\u00a00.0.14\u00a0\u03bcmol\/mL, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.006), leading to increased AMPK activity. Muscle energy deprivation was not caused by decreased mitochondrial activity as we found the respiratory complex II activity in vdr\u2212\/\u2212 muscles to be higher compared with WT (0.29\u00a0\u00b1\u00a00.007\u00a0mU\/\u03bcL vs. 0.16\u00a0\u00b1\u00a00.005\u00a0mU\/\u03bcL). vdr\u2212\/\u2212 mice had lower fasting blood glucose levels (95\u00a0\u00b1\u00a014.5\u00a0mg\/dL vs. 148.6\u00a0\u00b1\u00a06.1\u00a0mg\/dL, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.0017) while they exhibited hyperlactataemia (7.42\u00a0\u00b1\u00a00.31\u00a0nmol\/\u03bcL vs. 4.95\u00a0\u00b1\u00a00.44\u00a0nmol\/\u03bcL, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.0032), suggesting systemic energy deficiency in these mice. Insulin levels in these mice were significantly lower in response to intraperitoneal glucose injection (0.69\u00a0\u00b1\u00a00.08\u00a0pg\/mL vs. 1.11\u00a0\u00b1\u00a00.09\u00a0pg\/mL, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.024). Skeletal muscles of these mice exhibit glycogen storage disorder characterized by increased glycogen accumulation. The glycogen storage disorder in vdr\u2212\/\u2212 muscles is driven by increased glycogen synthase activity and decreased glycogen phosphorylase activity. Increased glycogenin expression supports higher levels of glycogen synthesis in these muscles.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The results presented show that lack of vitamin D signalling leads to a glycogen storage defect in the skeletal muscles, which leads to muscle energy deprivation. The inability of vdr\u2212\/\u2212 skeletal muscles to use glycogen leads to systemic defects in glucose homeostasis, which in turn leads to proteostasis defects in skeletal muscles and atrophy.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12841","type":"journal-article","created":{"date-parts":[[2021,12,8]],"date-time":"2021-12-08T08:49:27Z","timestamp":1638953367000},"page":"467-480","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Systemic ablation of vitamin D receptor leads to skeletal muscle glycogen storage disorder in mice"],"prefix":"10.1002","volume":"13","author":[{"given":"Anamica","family":"Das","sequence":"first","affiliation":[{"name":"Molecular Genetics Laboratory National Institute of Immunology  New Delhi India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suchitra D.","family":"Gopinath","sequence":"additional","affiliation":[{"name":"Translational Health Science and Technology Institute  Faridabad Haryana India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5266-2688","authenticated-orcid":false,"given":"Gopalakrishnan Aneeshkumar","family":"Arimbasseri","sequence":"additional","affiliation":[{"name":"Molecular Genetics Laboratory National Institute of Immunology  New Delhi 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