{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T02:45:25Z","timestamp":1772160325170,"version":"3.50.1"},"reference-count":46,"publisher":"Wiley","issue":"20","license":[{"start":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T00:00:00Z","timestamp":1750896000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["HL127691"],"award-info":[{"award-number":["HL127691"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["HL138007"],"award-info":[{"award-number":["HL138007"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FEBS Journal"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:p>\n                    A nonsense mutation in codon Glu\n                    <jats:sub>180<\/jats:sub>\n                    of the\n                    <jats:italic>TNNT1<\/jats:italic>\n                    gene, which encodes the slow skeletal muscle isoform of troponin T (ssTnT), causes a recessively inherited myopathy (the Amish Nemaline Myopathy, ANM). A ssTnT knockout (ssTnT\u2010KO) mouse model produced the loss of ssTnT function phenotypes of ANM with slow fiber atrophy and decreased fatigue resistance of soleus muscle. We further developed a\n                    <jats:italic>Tnnt1<\/jats:italic>\n                    p.Glu180* knock\u2010in (ANM\u2010KI) mouse model to precisely mimic the human mutation. In addition to reproducing the loss of function phenotypes, ANM\u2010KI mice exhibit more severe myopathy than that of ssTnT\u2010KO mice. Compared with wild\u2010type controls, ANM\u2010KI and ssTnT\u2010KO soleus muscles show different changes in gene expression profiles, of which gene ontology analysis indicated inflammatory activation in ANM\u2010KI soleus muscle. The mutant\n                    <jats:italic>Tnnt1<\/jats:italic>\n                    mRNA was readily detectable in ANM\u2010KI soleus muscle. However, the truncated ssTnT\n                    <jats:sub>1\u2013179<\/jats:sub>\n                    fragment cannot be detected in western blot, indicating its very low level due to the active proteolytic clearance of non\u2010myofilament\u2010incorporated TnT in muscle cells. Nonetheless, the more severe myopathic impacts of the ANM\u2010KI allele with more fiber number loss and muscle activity\/injury\u2010caused hypertrophy support a potent cytotoxicity of the ssTnT fragment, as shown in previous cell culture studies, which is further supported by activity\u2010dependent and age\u2010progressing myopathy with more active regeneration. The notion that non\u2010myofilament\u2010incorporated ssTnT fragments may potentially contribute to the pathogenesis and progression of myopathy merits further investigation.\n                  <\/jats:p>","DOI":"10.1111\/febs.70165","type":"journal-article","created":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T13:10:07Z","timestamp":1750943407000},"page":"5525-5539","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Potential cytotoxicity of truncated slow skeletal muscle troponin T (\n                    <scp>ssTnT<\/scp>\n                    ) in a loss of function\n                    <i>TNNT1<\/i>\n                    myopathy mouse model"],"prefix":"10.1111","volume":"292","author":[{"given":"Han\u2010Zhong","family":"Feng","sequence":"first","affiliation":[{"name":"Department of Physiology and Biophysics University of Illinois at Chicago  IL 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