{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T20:58:32Z","timestamp":1782939512881,"version":"3.54.5"},"reference-count":40,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T00:00:00Z","timestamp":1761782400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T00:00:00Z","timestamp":1761782400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100012681","name":"College of Natural Resources and Sciences, Humboldt State University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100012681","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005156","name":"Alexander von Humboldt-Stiftung","doi-asserted-by":"publisher","award":["Friedrich Wilhelm Bessel award"],"award-info":[{"award-number":["Friedrich Wilhelm Bessel award"]}],"id":[{"id":"10.13039\/100005156","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["DFG, HE1853\/15\u20101"],"award-info":[{"award-number":["DFG, HE1853\/15\u20101"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["DFG, SCHR 562\/19\u20101"],"award-info":[{"award-number":["DFG, SCHR 562\/19\u20101"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["CL 381\/12\u20101"],"award-info":[{"award-number":["CL 381\/12\u20101"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Mutations in the desmin gene cause skeletal myopathies and cardiomyopathies. The objective of this study was to elucidate the molecular pathology induced by the expression of R405W mutant desmin in murine skeletal muscle.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A comprehensive characterization of the skeletal muscle pathology in hetero\u2010 and homozygous R405W desmin knock\u2010in mice was performed. This included grip strength, blood acylcarnitine and amino acid, histological, ultrastructural, immunofluorescence, immunoblot, ribosomal stalling, RNA sequencing and proteomic analyses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Both hetero\u2010 and homozygous R405W desmin knock\u2010in mice showed classical myopathological features of a myofibrillar myopathy with desmin\u2010positive protein aggregation, degenerative changes of the myofibrillar apparatus and mitochondrial alterations. Muscle weakness and increased blood concentrations of acylcarnitines and amino acids were only present in homozygous animals. During its translation, mutant desmin did not induce terminal ribosomal stalling. Analyses of RNA sequencing and proteomic data from soleus muscle of 3\u2010month\u2010old mice depicted 59 up\u2010 and 3 down\u2010regulated mRNAs and 101 up\u2010 and 18 down\u2010regulated proteins that were shared between the heterozygous and homozygous genotypes in the respective omics datasets compared to the wild\u2010type genotype. Combined analysis of the omics data demonstrated 187 significantly dysregulated candidates distributed across four groups of regulation. A down\u2010regulation on the mRNA and protein levels was observed for a multitude of mitochondrial proteins including essential proton gradient\u2010dependent carriers. Up\u2010regulation on both omics levels was present for the transcription factor Mlf1, which is a binding partner of protein quality control related Dnajb6. Down\u2010regulated on mRNA but up\u2010regulated on the protein level was the sarcomeric lesion marker Xirp2 (xin actin\u2010binding repeat\u2010containing protein 2), whereas Ces2c (acylcarnitine hydrolase) was regulated in the opposite way.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The present study demonstrates that the expression of mutant desmin results in a myofibrillar myopathy in hetero\u2010 and homozygous R405W desmin knock\u2010in mice. Combined morphological, transcriptomic and proteomic analyses helped decipher the complex pattern of early pathological changes induced by the expression of mutant desmin. Our findings highlight the importance of major mitochondrial alterations, including essential proton gradient\u2010dependent carriers as well as Dnajb6\u2010related protein quality control and Xin\u2010related myofibrillar damage, in the molecular pathogenesis of desminopathies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.70094","type":"journal-article","created":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T10:27:09Z","timestamp":1761820029000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["R405W Desmin Knock\u2010In Mice Highlight Alterations of Mitochondria, Protein Quality Control and Myofibrils in Myofibrillar Myopathy"],"prefix":"10.1002","volume":"16","author":[{"given":"Sabrina","family":"Batonnet\u2010Pichon","sequence":"first","affiliation":[{"name":"Basic and Translational Myology, Unit of Functional and Adaptive Biology Universit\u00e9 Paris Cit\u00e9\/CNRS UMR 8251  Paris 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