{"doi":"10.1111/febs.70165","title":"Potential cytotoxicity of truncated slow skeletal muscle troponin T ( <scp>ssTnT</scp> ) in a loss of function <i>TNNT1</i> myopathy mouse model","abstract":"A nonsense mutation in codon Glu 180 of the TNNT1 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‐KO) 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 Tnnt1 p.Glu180* knock‐in (ANM‐KI) mouse model to precisely mimic the human mutation. In addition to reproducing the loss of function phenotypes, ANM‐KI mice exhibit more severe myopathy than that of ssTnT‐KO mice. Compared with wild‐type controls, ANM‐KI and ssTnT‐KO soleus muscles show different changes in gene expression profiles, of which gene ontology analysis indicated inflammatory activation in ANM‐KI soleus muscle. The mutant Tnnt1 mRNA was readily detectable in ANM‐KI soleus muscle. However, the truncated ssTnT 1–179 fragment cannot be detected in western blot, indicating its very low level due to the active proteolytic clearance of non‐myofilament‐incorporated TnT in muscle cells. Nonetheless, the more severe myopathic impacts of the ANM‐KI allele with more fiber number loss and muscle activity/injury‐caused hypertrophy support a potent cytotoxicity of the ssTnT fragment, as shown in previous cell culture studies, which is further supported by activity‐dependent and age‐progressing myopathy with more active regeneration. The notion that non‐myofilament‐incorporated ssTnT fragments may potentially contribute to the pathogenesis and progression of myopathy merits further investigation.","journal":"FEBS Journal","year":2025,"id":553308,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9633,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":602340,"name":"Kevin A. Strauss","orcid":"0000-0002-6429-8657","position":1,"is_corresponding":false},{"id":349855,"name":"Jian‐Ping Jin","orcid":"0000-0001-9932-1063","position":2,"is_corresponding":false},{"id":435150,"name":"Han‐Zhong Feng","orcid":null,"position":0,"is_corresponding":true}],"reference_count":47,"raw_metadata":null,"created_at":"2026-07-19T02:54:41.819682Z","pmid":"40569886","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}