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Notably, alterations in thyroid hormone (TH) levels during ageing are intricately linked to the development of sarcopenia. In skeletal muscle, the primary action of TH is mediated through the thyroid hormone receptor alpha (TR\u03b1). Emerging evidence suggests that decreased TR\u03b1 expression may precipitate mitochondrial dysfunction in ageing skeletal muscle tissues. Yet, the precise mechanisms and the potential causative role of TR\u03b1 deficiency in sarcopenia are not fully understood. This study suggests that TR\u03b1 may regulate mitochondrial calcium (Ca\n                    <jats:sup>2+<\/jats:sup>\n                    ) transport across membranes by targeting the inositol 1,4,5\u2010trisphosphate receptor 1 (IP3R1), as evidenced by ChIP\u2010seq and RNA\u2010seq analyses. Experiments using naturally aged mice, skeletal muscle\u2010specific TR\u03b1 knockout (SKT) mice, and C2C12 myoblasts were conducted to investigate this process further. Findings include increased IP3R1, mitochondria\u2010associated endoplasmic reticulum membranes (MAM), and mitochondrial Ca\n                    <jats:sup>2+<\/jats:sup>\n                    in aged skeletal muscle. Additionally, SKT mice exhibited smaller muscle fibres, increased IP3R1 and MAM, and mitochondrial dysfunction. ChIP\u2010qPCR and TR\u03b1 manipulation in C2C12 cells showed that TR\u03b1 negatively regulates IP3R1 transcription. Moreover, TR\u03b1 knockdown cells exhibited increased Ca\n                    <jats:sup>2+<\/jats:sup>\n                    transfer in MAM and mitochondrial dysfunction, which was ameliorated by the IP3R1 inhibitor 2\u2010aminoethoxydiphenyl borate. Reintroduction of TR\u03b1 improved IP3R1\u2010mediated mitochondrial Ca\n                    <jats:sup>2+<\/jats:sup>\n                    overload in aged cells. Our findings uncover a novel mechanism by which TR\u03b1 deficiency induces mitochondrial Ca\n                    <jats:sup>2+<\/jats:sup>\n                    overload through IP3R1\u2010mediated Ca\n                    <jats:sup>2+<\/jats:sup>\n                    transfer in MAM, exacerbating skeletal muscle atrophy during ageing. The TR\u03b1\/IP3R1 pathway in MAM Ca\n                    <jats:sup>2+<\/jats:sup>\n                    transfer presents a potential therapeutic target for sarcopenia.\n                  <\/jats:p>","DOI":"10.1111\/cpr.70120","type":"journal-article","created":{"date-parts":[[2025,8,25]],"date-time":"2025-08-25T05:34:47Z","timestamp":1756100087000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Ageing\u2010Dependent Thyroid Hormone Receptor \u03b1 Reduction Activates\n                    <scp>IP3R1<\/scp>\n                    \u2010Meditated Ca\n                    <sup>2+<\/sup>\n                    Transfer in\n                    <scp>MAM<\/scp>\n                    and Exacerbates Skeletal Muscle Atrophy in Mice"],"prefix":"10.1111","volume":"59","author":[{"given":"Runqing","family":"Shi","sequence":"first","affiliation":[{"name":"Department of Gerontology The First Affiliated Hospital With Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusheng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Gerontology The First Affiliated Hospital With Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gong","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Gerontology The First Affiliated Hospital With Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiru","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Gerontology The First Affiliated Hospital With Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Gerontology The First Affiliated Hospital With Nanjing Medical University  Nanjing 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