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Keck Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000888","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Genomics"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Titinopathies are inherited muscular diseases triggered by genetic mutations in the titin gene. Muscular dystrophy with myositis (<jats:italic>mdm<\/jats:italic>) is one such disease caused by a LINE repeat insertion, leading to exon skipping and an 83-amino acid residue deletion in the N2A-PEVK region of mouse titin. This region has been implicated in a number of titin\u2014titin ligand interactions, hence are important for myocyte signaling and health. Mice with this <jats:italic>mdm<\/jats:italic> mutation develop a severe and progressive muscle degeneration. The range of phenotypic differences observed in <jats:italic>mdm<\/jats:italic> mice shows that the deletion of this region induces a cascade of transcriptional changes extending to numerous signaling pathways affected by the titin filament. Previous research has focused on correlating phenotypic differences with muscle function in <jats:italic>mdm<\/jats:italic> mice. These studies have provided understanding of the downstream physiological effects resulting from the <jats:italic>mdm<\/jats:italic> mutation but only provide insights on processes that can be physiologically observed and measured. We used differential gene expression (DGE) to compare the transcriptomes of extensor digitorum longus (EDL), psoas and soleus muscles from wild-type and <jats:italic>mdm<\/jats:italic> mice to develop a deeper understand of these tissue-specific responses.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>The overall expression pattern observed shows a well-differentiated transcriptional signature in <jats:italic>mdm<\/jats:italic> muscles compared to wild type. Muscle-specific clusters observed within the <jats:italic>mdm<\/jats:italic> transcriptome highlight the level of variability of each muscle to the deletion. Differential gene expression and weighted gene co-expression network analysis showed a strong directional response in oxidative respiration-associated mitochondrial genes, which aligns with the poor shivering and non-shivering thermogenesis previously observed. Sln, which is a marker associated with shivering and non-shivering thermogenesis, showed the strongest expression change in fast-fibered muscles. No drastic changes in MYH expression levels were reported, which indicated an absence of major fiber-type switching events. Overall expression shifts in MYH isoforms, MARPs, and extracellular matrix associated genes demonstrated the transcriptional complexity associated with <jats:italic>mdm<\/jats:italic> mutation. The expression alterations in mitochondrial respiration and metabolism related genes in the <jats:italic>mdm<\/jats:italic> muscle dominated over other transcriptomic changes, and likely account for the late stage cellular responses in the <jats:italic>mdm<\/jats:italic> muscles.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>We were able to demonstrate that the complex nature of <jats:italic>mdm<\/jats:italic> mutation extends beyond a simple rearrangement in titin gene. EDL, psoas and soleus exemplify unique response modes observed in skeletal muscles with <jats:italic>mdm<\/jats:italic> mutation. Our data also raises the possibility that failure to maintain proper energy homeostasis in <jats:italic>mdm<\/jats:italic> muscles may contribute to the pathogenesis of the degenerative phenotype in <jats:italic>mdm<\/jats:italic> mice. Understanding the full disease-causing molecular cascade is difficult using bulk RNA sequencing techniques due to intricate nature of the disease. The development of the <jats:italic>mdm<\/jats:italic> phenotype is temporally and spatially regulated, hence future studies should focus on single fiber level investigations.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12864-022-08873-2","type":"journal-article","created":{"date-parts":[[2022,9,17]],"date-time":"2022-09-17T08:14:44Z","timestamp":1663402484000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Transcriptomic profiles of muscular dystrophy with myositis (mdm) in extensor digitorum longus, psoas, and soleus muscles from mice"],"prefix":"10.1186","volume":"23","author":[{"given":"Pabodha","family":"Hettige","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Uzma","family":"Tahir","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kiisa C.","family":"Nishikawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew J.","family":"Gage","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2022,9,17]]},"reference":[{"key":"8873_CR1","doi-asserted-by":"publisher","unstructured":"Nishikawa K, Lindstedt SL, Hessel A, Mishra D. 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