{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,5,24]],"date-time":"2025-05-24T04:14:58Z","timestamp":1748060098884,"version":"3.41.0"},"reference-count":31,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2024,10,28]],"date-time":"2024-10-28T00:00:00Z","timestamp":1730073600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82271436"],"award-info":[{"award-number":["82271436"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007129","name":"Shandong Provincial Natural Science Foundation","doi-asserted-by":"publisher","award":["ZR2022MH190"],"award-info":[{"award-number":["ZR2022MH190"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Qingdao Science and Technology Benefit People Demonstration Guide Special Projecta","award":["22-8-7-smjk-1-nsh"],"award-info":[{"award-number":["22-8-7-smjk-1-nsh"]}]},{"name":"Taishan Scholars Program for Young Experts of Shandong Province","award":["tsqn202306347"],"award-info":[{"award-number":["tsqn202306347"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,5,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Limb-girdle muscular dystrophy R7 is a rare genetic disease caused by homozygous or compound heterozygous variants in the titin-cap (TCAP) gene that results in the absence of the protein telethonin. The primary pathological features of limb-girdle muscular dystrophy R7 are fibre size variation, nuclear centralization and abnormal mitochondrial distribution. The mechanisms underlying this disease are unclear and there is currently no specific treatment for limb-girdle muscular dystrophy R7.<\/jats:p>\n               <jats:p>This study established a Tcap-deficient mouse model to explore the disease mechanism of mitochondria dislocation and potential therapeutic strategies. We used methods such as proteomics, immunofluorescence, histopathological staining and western blotting to explore the mechanism of mitochondrial dislocation. Moreover, in the quest for a prospective therapeutic intervention for this disorder, the adeno-associated virus (AAV) serotype 2\/9 was employed to deliver the Tcap gene into the muscles of these mice, facilitating preclinical experimentation. After 2 months and 7 months, the muscular phenotype was evaluated and selected mice were humanely euthanized for subsequent molecular and histological analysis.<\/jats:p>\n               <jats:p>The phenotype of Tcap\u2212\/\u2212 mice mimicked that observed in individuals diagnosed with limb-girdle muscular dystrophy R7. This study elucidated the mechanism of mitochondrial dislocation in limb-girdle muscular dystrophy R7. Through our in vitro experiments, we discovered that telethonin aids in preserving the integrity of desmin by preventing truncation at the N-terminus. Additionally, telethonin combined with desmin and co-localized at the Z-disc. Research has shown that the Tcap gene plays a crucial role in controlling the desmin cytoskeleton organization. The absence of telethonin leads to a collapsed desmin cytoskeleton. This causes disorganization of the mitochondrial network, leading to mitochondrial dysfunction. In addition, the study investigated the efficacy of AAV-mediated Tcap replacement in Tcap\u2212\/\u2212 mice. By intramuscular delivery of AAV, we observed dramatic improvements in muscle phenotype, muscle pathology, CK levels, muscle MRI, mitochondrial network organization and mitochondrial function.<\/jats:p>\n               <jats:p>The results of this study demonstrated that telethonin deficiency led to desmin cytoskeleton collapse that caused mitochondrial dislocation. AAV-mediated replacement therapy could be a promising safe and efficient treatment option for limb-girdle muscular dystrophy R7. The study highlights the potential of AAV-mediated replacement therapy for specific types of limb-girdle muscular dystrophy.<\/jats:p>","DOI":"10.1093\/brain\/awae351","type":"journal-article","created":{"date-parts":[[2024,10,29]],"date-time":"2024-10-29T06:14:19Z","timestamp":1730182459000},"page":"1680-1694","source":"Crossref","is-referenced-by-count":0,"title":["AAV-based TCAP delivery rescues mitochondria dislocation in limb-girdle muscular dystrophy R7"],"prefix":"10.1093","volume":"148","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7199-0297","authenticated-orcid":false,"given":"Xiaoqing","family":"Lv","sequence":"first","affiliation":[{"name":"Department of Neurology, Research Institute of Neuromuscular and Neurodegenerative Diseases, Qilu Hospital of Shandong University , Shandong Provincial Key Laboratory of Mitochondrial Medicine and Rare Diseases, Jinan, Shandong 250012 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School of Medicine, Shandong University , Jinan, Shandong 250012 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4148-625X","authenticated-orcid":false,"given":"He","family":"Lv","sequence":"additional","affiliation":[{"name":"Department of Neurology, Peking University First Hospital , Beijing 100034 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kai","family":"Shao","sequence":"additional","affiliation":[{"name":"Mitochondrial Medicine Laboratory, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University , Qingdao, Shandong 266035 ,","place":["China"]},{"name":"Department of Clinical Laboratory, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University , Qingdao 266000 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sushan","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Neurology and Huashan Rare Disease Center, Huashan Hospital, Shanghai Medical College, Fudan University, National Center for Neurological Disorders , Shanghai 200040 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dandan","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Neurology and Research Institute of Neuromuscular and Neurodegenerative Diseases, Qilu Hospital of Shandong University , Jinan, Shandong 250012 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2191-5184","authenticated-orcid":false,"given":"Chuanzhu","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Neurology, Research Institute of Neuromuscular and Neurodegenerative Diseases, Qilu Hospital of Shandong University , Shandong Provincial Key Laboratory of Mitochondrial Medicine and Rare Diseases, Jinan, Shandong 250012 ,","place":["China"]},{"name":"Department of Neurology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University , Qingdao 266000 ,","place":["China"]},{"name":"Mitochondrial Medicine Laboratory, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University , Qingdao, Shandong 266035 ,","place":["China"]},{"name":"Key Laboratory for Experimental Teratology of the Ministry of Education, Brain Science Research Institute, Shandong University , Jinan, Shandong 250000 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pengfei","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Neurology, Research Institute of Neuromuscular and Neurodegenerative Diseases, Qilu Hospital of Shandong University , Shandong Provincial Key Laboratory of Mitochondrial Medicine and Rare Diseases, Jinan, Shandong 250012 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