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The PDZ-LIM proteins have been proposed to function as adaptors in transducing mechanical signals to preserve the Z-disc structure, however the underlying mechanisms remain poorly understood. Here, we show that LDB3, a well-characterized striated muscle PDZ-LIM protein, modulates mechanical stress signaling through interactions with the mechanosensing domain in filamin C, its chaperone HSPA8, and PKC\u03b1 in the Z-disc of skeletal muscle. Studies of <jats:italic>Ldb3<\/jats:italic><jats:sup><jats:italic>Ala165Val\/+<\/jats:italic><\/jats:sup> mice indicate that the myopathy-associated LDB3 p.Ala165Val mutation triggers early aggregation of filamin C and its chaperones at muscle Z-disc before aggregation of the mutant protein. The mutation causes protein aggregation and eventually Z-disc myofibrillar disruption by impairing PKC\u03b1 and TSC2-mTOR, two important signaling pathways regulating protein stability and disposal of damaged cytoskeletal components at a major mechanosensor hub in the Z-disc of skeletal muscle.<\/jats:p>","DOI":"10.1038\/s42003-021-01864-1","type":"journal-article","created":{"date-parts":[[2021,3,19]],"date-time":"2021-03-19T13:04:20Z","timestamp":1616159060000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Myopathy associated LDB3 mutation causes Z-disc disassembly and protein aggregation through PKC\u03b1 and TSC2-mTOR downregulation"],"prefix":"10.1038","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8753-7385","authenticated-orcid":false,"given":"Pankaj","family":"Pathak","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3328-8122","authenticated-orcid":false,"given":"Yotam","family":"Blech-Hermoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kalpana","family":"Subedi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Mpamugo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charissa","family":"Obeng-Nyarko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Ohman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilda","family":"Molloy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2912-1872","authenticated-orcid":false,"given":"Malcolm","family":"Kates","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Hale","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stacey","family":"Stauffer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9333-870X","authenticated-orcid":false,"given":"Shyam K.","family":"Sharan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5131-7767","authenticated-orcid":false,"given":"Ami","family":"Mankodi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,3,19]]},"reference":[{"key":"1864_CR1","doi-asserted-by":"publisher","first-page":"13591","DOI":"10.1074\/jbc.R200021200","volume":"278","author":"JM Ervasti","year":"2003","unstructured":"Ervasti, J. 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