{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T14:43:27Z","timestamp":1781880207334,"version":"3.54.5"},"reference-count":40,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:00:00Z","timestamp":1760140800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003407","name":"MIUR","doi-asserted-by":"crossref","award":["D.3.2.2015"],"award-info":[{"award-number":["D.3.2.2015"]}],"id":[{"id":"10.13039\/501100003407","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003407","name":"MIUR","doi-asserted-by":"crossref","award":["D.1.2017"],"award-info":[{"award-number":["D.1.2017"]}],"id":[{"id":"10.13039\/501100003407","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Magnesium (Mg2+) is a key regulator of cellular biochemical processes and an essential cofactor in skeletal muscle physiology. Although Mg2+ deficiency has been linked to reduced muscle strength, its role in the regulation of calcium (Ca2+) signaling and in inflammation remains incompletely understood. In this study, we examined the effects of Mg2+ availability using the murine myoblast cell line C2C12. Cells were differentiated under low, normal, or high Mg2+ conditions, and myotube formation, intracellular Ca2+ fluxes, and resistance to inflammatory stimuli were assessed. Mg2+ deficiency impaired myotube differentiation, while Mg2+ supplementation preserved Ca2+ response during stimulation and contributed to protect myotubes against inflammation-induced damage. Collectively, these findings highlight a dual role of Mg2+ in sustaining functional performance under repeated stress and protecting myotubes against inflammatory injury. This study supports the importance of adequate dietary Mg2+ intake as a potential strategy to mitigate muscle loss associated with aging and chronic inflammation.<\/jats:p>","DOI":"10.3390\/ijms26209912","type":"journal-article","created":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T16:13:03Z","timestamp":1760717583000},"page":"9912","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Magnesium Preserves Calcium Homeostasis and Contributes to Protect Myotubes from Inflammation-Induced Damage"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4802-7312","authenticated-orcid":false,"given":"Giuseppe","family":"Pietropaolo","sequence":"first","affiliation":[{"name":"Dipartimento di Medicina e Chirurgia Traslazionale, Fondazione Policlinico Universitario A. Gemelli IRCCS, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"},{"name":"IRCCS Neuromed, 86077 Pozzilli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8785-9891","authenticated-orcid":false,"given":"Sara","family":"Castiglioni","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Biomediche e Cliniche, Universit\u00e0 di Milano, 20157 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6326-9221","authenticated-orcid":false,"given":"Jeanette A.","family":"Maier","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Biomediche e Cliniche, Universit\u00e0 di Milano, 20157 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1361-1049","authenticated-orcid":false,"given":"Federica I.","family":"Wolf","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina e Chirurgia Traslazionale, Fondazione Policlinico Universitario A. Gemelli IRCCS, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Trapani","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina e Chirurgia Traslazionale, Fondazione Policlinico Universitario A. Gemelli IRCCS, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"},{"name":"Departmental Faculty of Medicine, UniCamillus, Saint Camillus International University of Medical Sciences, 00131 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1152\/physrev.00012.2014","article-title":"Magnesium in Man: Implications for Health and Disease","volume":"95","author":"Hoenderop","year":"2015","journal-title":"Physiol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1998","DOI":"10.1056\/NEJMra1510603","article-title":"Magnesium Disorders","volume":"390","author":"Touyz","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1016\/j.bbadis.2007.03.009","article-title":"TRPM6 and TRPM7\u2014Gatekeepers of human magnesium metabolism","volume":"1772","author":"Schlingmann","year":"2007","journal-title":"Biochim. Biophys. Acta (BBA)\u2014Mol. Basis Dis."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Luongo, F., Pietropaolo, G., Gautier, M., Dhennin-Duthille, I., Ouadid-Ahidouch, H., Wolf, F.I., and Trapani, V. (2018). TRPM6 is Essential for Magnesium Uptake and Epithelial Cell Function in the Colon. Nutrients, 10.","DOI":"10.3390\/nu10060784"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.semcdb.2020.11.002","article-title":"Magnesium and inflammation: Advances and perspectives","volume":"115","author":"Maier","year":"2021","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2198","DOI":"10.1093\/ibd\/izy186","article-title":"Dietary Magnesium Alleviates Experimental Murine Colitis Through Upregulation of the Transient Receptor Potential Melastatin 6 Channel","volume":"24","author":"Trapani","year":"2018","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1186\/s41043-023-00423-0","article-title":"A narrative review on the role of magnesium in immune regulation, inflammation, infectious diseases, and cancer","volume":"42","author":"Ashique","year":"2023","journal-title":"J. Health Popul. Nutr."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"707","DOI":"10.5114\/aoms.2018.75719","article-title":"Effect of magnesium supplements on serum C-reactive protein: A systematic review and meta-analysis","volume":"14","author":"Mazidi","year":"2018","journal-title":"Arch. Med. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1684\/mrh.2024.0526","article-title":"The central role of magnesium in skeletal muscle: From myogenesis to performance","volume":"37","author":"Castiglioni","year":"2024","journal-title":"Magnes. Res."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Zocchi, M., Locatelli, L., Zuccotti, G.V., Mazur, A., B\u00e9chet, D., Maier, J.A., and Castiglioni, S. (2022). Magnesium Homeostasis in Myogenic Differentiation\u2014A Focus on the Regulation of TRPM7, MagT1 and SLC41A1 Transporters. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031658"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"421","DOI":"10.2170\/jjphysiol.48.421","article-title":"Cytoplasmic Free Concentrations of Ca2+ and Mg2+ in Skeletal Muscle Fibers at Rest and during Contraction","volume":"48","author":"Konishi","year":"1998","journal-title":"Jpn. J. Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"9408","DOI":"10.1021\/bi060623a","article-title":"Insights into the Regulation of the Ryanodine Receptor: Differential Effects of Mg2+ and Ca2+ on ATP Binding","volume":"45","author":"Dias","year":"2006","journal-title":"Biochemistry"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1002\/cbf.1790","article-title":"Magnesium deficiency up-regulates Myod expression in rat skeletal muscle and C2C12 myogenic cells","volume":"29","author":"Furutani","year":"2011","journal-title":"Cell Biochem. Funct."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Zocchi, M., B\u00e9chet, D., Mazur, A., Maier, J.A., and Castiglioni, S. (2021). Magnesium Influences Membrane Fusion during Myogenesis by Modulating Oxidative Stress in C2C12 Myoblasts. Nutrients, 13.","DOI":"10.3390\/nu13041049"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"585S","DOI":"10.1093\/ajcn\/72.2.585S","article-title":"Magnesium, zinc, and chromium nutriture and physical activity","volume":"72","author":"Lukaski","year":"2000","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12877-022-03522-5","article-title":"Association between oral intake magnesium and sarcopenia: A cross-sectional study","volume":"22","author":"Yang","year":"2022","journal-title":"BMC Geriatr."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"832","DOI":"10.2174\/138161210790883679","article-title":"Magnesium and Aging","volume":"16","author":"Barbagallo","year":"2010","journal-title":"Curr. Pharm. Des."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"974","DOI":"10.3945\/ajcn.113.080168","article-title":"Effect of oral magnesium supplementation on physical performance in healthy elderly women involved in a weekly exercise program: A randomized controlled trial","volume":"100","author":"Veronese","year":"2014","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Bayle, D., Coudy-Gandilhon, C., Gueugneau, M., Castiglioni, S., Zocchi, M., Maj-Zurawska, M., Palinska-Saadi, A., Mazur, A., B\u00e9chet, D., and Maier, J.A. (2021). Magnesium Deficiency Alters Expression of Genes Critical for Muscle Magnesium Homeostasis and Physiology in Mice. Nutrients, 13.","DOI":"10.3390\/nu13072169"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s13395-021-00280-7","article-title":"The SarcoEndoplasmic Reticulum Calcium ATPase (SERCA) Pump: A Potential Target for Intervention in Aging and Skeletal Muscle Pathologies","volume":"11","author":"Xu","year":"2021","journal-title":"Skelet. Muscle"},{"key":"ref_21","first-page":"180","article-title":"Update on the relationship between magnesium and exercise","volume":"19","author":"Nielsen","year":"2006","journal-title":"Magnes. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1016\/0891-5849(95)02180-9","article-title":"Functional alterations in sarcoplasmic reticulum membranes of magnesium-deficient rat skeletal muscle as consequences of free radical-mediated process","volume":"20","author":"Astier","year":"1996","journal-title":"Free Radic. Biol. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1111\/j.1474-9726.2011.00706.x","article-title":"Store-operated calcium entry remains fully functional in aged mouse skeletal muscle despite a decline in STIM1 protein expression","volume":"10","author":"Edwards","year":"2011","journal-title":"Aging Cell"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"621","DOI":"10.18632\/aging.100335","article-title":"Store-Operated Ca2+ Entry (SOCE) Contributes to Normal Skeletal Muscle Contractility in young but not in aged skeletal muscle","volume":"3","author":"Thornton","year":"2011","journal-title":"Aging"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1093\/jn\/125.5.1205","article-title":"Dietary Magnesium Deficiency in Rats Enhances Free Radical Production in Skeletal Muscle","volume":"125","author":"Rock","year":"1995","journal-title":"J. Nutr."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Cepeda, V., R\u00f3denas-Munar, M., Garc\u00eda, S., Bouzas, C., and Tur, J.A. (2025). Unlocking the Power of Magnesium: A Systematic Review and Meta-Analysis Regarding Its Role in Oxidative Stress and Inflammation. Antioxidants, 14.","DOI":"10.3390\/antiox14060740"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1002\/jbmr.2692","article-title":"Dietary Magnesium Is Positively Associated With Skeletal Muscle Power and Indices of Muscle Mass and May Attenuate the Association Between Circulating C-Reactive Protein and Muscle Mass in Women","volume":"31","author":"Welch","year":"2015","journal-title":"J. Bone Miner. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e12423","DOI":"10.15252\/emmm.202012423","article-title":"Dietary magnesium supplementation improves lifespan in a mouse model of progeria","volume":"12","year":"2020","journal-title":"EMBO Mol. Med."},{"key":"ref_29","first-page":"103","article-title":"Mg deficiency results in modulation of serum lipids, glutathione, and NO synthase isozyme activation in cardiovascular tissues: Relevance to de novo synthesis of ceramide, serum Mg and atherogenesis","volume":"4","author":"Shah","year":"2011","journal-title":"Int. J. Clin. Exp. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/2044-5040-2-2","article-title":"TNF-\u03b1- and tumor-induced skeletal muscle atrophy involves sphingolipid metabolism","volume":"2","author":"Zufferli","year":"2012","journal-title":"Skelet. Muscle"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Kaur, N., Gupta, P., Dutt, V., Sharma, O., Gupta, S., Dua, A., Injeti, E., and Mittal, A. (2024). Cinnamaldehyde attenuates TNF-\u03b1 induced skeletal muscle loss in C2C12 myotubes regulation of protein synthesis, proteolysis, oxidative stress and inflammation. Arch. Biochem. Biophys., 753.","DOI":"10.1016\/j.abb.2024.109922"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"486","DOI":"10.3892\/mmr.2021.12125","article-title":"Pyropia yezoensis protein protects against TNF-\u03b1-induced myotube atrophy in C2C12 myotubes via the NF-\u03baB signaling pathway","volume":"24","author":"Lee","year":"2021","journal-title":"Mol. Med. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1016\/j.bbrc.2015.02.026","article-title":"TNF alpha inhibits myogenic differentiation of C2C12 cells through NF-\u03baB activation and impairment of IGF-1 signaling pathway","volume":"458","author":"Zhao","year":"2015","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Powr\u00f3zek, T., Pigo\u0144-Zaj\u0105c, D., Mazurek, M., Otieno, M.O., Rahnama-Hezavah, M., and Ma\u0142ecka-Massalska, T. (2022). TNF-\u03b1 Induced Myotube Atrophy in C2C12 Cell Line Uncovers Putative Inflammatory-Related lncRNAs Mediating Muscle Wasting. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23073878"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1038\/s41420-023-01365-6","article-title":"TNF-\u03b1 contributes to sarcopenia through caspase-8\/caspase-3\/GSDME-mediated pyroptosis","volume":"9","author":"Wu","year":"2023","journal-title":"Cell Death Discov."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"10327","DOI":"10.1074\/jbc.M511131200","article-title":"Tumor Necrosis Factor-like Weak Inducer of Apoptosis Inhibits Skeletal Myogenesis through Sustained Activation of Nuclear Factor-\u03baB and Degradation of MyoD Protein","volume":"281","author":"Dogra","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"101987","DOI":"10.1016\/j.xpro.2022.101987","article-title":"Measuring SERCA-mediated calcium uptake in mouse muscle homogenates","volume":"4","author":"Geromella","year":"2023","journal-title":"STAR Protoc."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1093\/ajcn\/84.2.419","article-title":"Magnesium and muscle performance in older persons: The InCHIANTI study1\u20133","volume":"84","author":"Dominguez","year":"2006","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"25","DOI":"10.2147\/JIR.S136742","article-title":"Magnesium deficiency and increased inflammation: Current perspectives","volume":"11","author":"Nielsen","year":"2018","journal-title":"J. Inflamm. Res."},{"key":"ref_40","first-page":"156","article-title":"Hypomagnesemia and its relation with chronic low-grade inflammation in obesity","volume":"63","author":"Cruz","year":"2017","journal-title":"Front. Public Health"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/20\/9912\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,18]],"date-time":"2025-10-18T04:17:15Z","timestamp":1760761035000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/20\/9912"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,11]]},"references-count":40,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2025,10]]}},"alternative-id":["ijms26209912"],"URL":"https:\/\/doi.org\/10.3390\/ijms26209912","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,11]]}}}