2026-08-29T09:24:34Zhttps://repisalud.isciii.es/rest/oai/request
oai:repisalud.isciii.es:20.500.12105/270592025-12-18T12:57:37Zcom_20.500.12105_19586com_20.500.12105_2202col_20.500.12105_19587
Repisalud author Silva-Rojas, Roberto author Vicente, Natalia author Gavilán-Herrera, Manuel author Labrador-Cantarero, Verónica author Sicilia, Jon author Giménez-Sáez, Olga author Dumitru, Andra C author Sánchez, Mateo I author Gato-Vilaseca, Mara author Velázquez-Carreras, Diana author López, Juan Antonio author Vázquez, Jesús author Herrero-Galán, Elías author López-Unzu, Miguel A author Pricolo, Maria Rosaria author Alegre-Cebollada, Jorge funder Unión Europea. Comisión Europea. H2020 funder Instituto de Salud Carlos III funder Ministerio de Ciencia, Innovación y Universidades (España) funder Fundación ProCNIC funder Fundación La Caixa funder European Molecular Biology Organization funder Unión Europea. Comisión Europea. NextGenerationEU funder Unión Europea. Comisión Europea. European Research Council (ERC) 2025-12-16T15:55:32Z 2025-12-16T15:55:32Z 2025-10 Nat Biomed Eng. 2025 Oct;9(10):1758-1774. NATURE BIOMEDICAL ENGINEERING 40473933 https://hdl.handle.net/20.500.12105/27059 Titin, the elastic protein scaffold of muscle sarcomeres, has multifunctional roles in mechanosignalling and is implicated in muscle disease. However, the consequences of disrupting titin's mechanical function in vivo remain incompletely understood. Here, by leveraging site-directed polypeptide severing as a 'mechanical knock-out' method for abolishing force transmission across titin, we show that the loss of titin tension in homozygous mechanically knocked-out muscles reduces force generation and induces severe atrophy and widespread transcriptional dysregulation. Although mechanically knocked-out myofibres persist, they shrink and undergo progressive sarcomere depletion, which correlates with the rapid upregulation of muscle-specific RING finger protein 1 (MuRF1) and with altered levels of other titin-associated atrophy regulators. The affected fibres also exhibit mitochondrial aggregation and myonuclei internalization, preceded by desmin mislocalization. Heterozygous mechanically knocked-out muscles show milder phenotypes that closely resemble titin-related human myopathy. Our findings suggest that slack titin molecules drive muscle disease, potentially through mechanisms shared with other mechanical proteins. eng Mechanically knocking out titin reveals protein tension loss as a trigger of muscle disease. research article 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 URL https://repisalud.isciii.es/bitstreams/c0a23788-99f5-4b6e-b0d2-0f705bde7588/download File MD5 d416572a8ce40add6f11984f7515abb3 2574136 application/pdf A mechanical knock-out system uncovers_Nat Biomed Eng_2025 .pdf URL https://repisalud.isciii.es/bitstreams/29d61b85-78af-40cd-833d-b9c068b8d47e/download File MD5 53f835872e192be237cf9c7900773730 2207744 application/pdf A mechanical knock-out system uncovers__Supplementary information_Nat Biomed Eng_2025 .pdf