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1476-468763980542025MarNatureNatureTranscriptional adaptation upregulates utrophin in Duchenne muscular dystrophy.493502493-50210.1038/s41586-024-08539-xDuchenne muscular dystrophy (DMD) is a muscle-degenerating disease caused by mutations in the DMD gene, which encodes the dystrophin protein1,2. Utrophin (UTRN), the genetic and functional paralogue of DMD, is upregulated in some DMD patients3-5. To further investigate this UTRN upregulation, we first developed an inducible messenger RNA (mRNA) degradation system for DMD by introducing a premature termination codon (PTC) in one of its alternatively spliced exons. Inclusion of the PTC-containing exon triggers DMD mutant mRNA decay and UTRN upregulation. Notably, blocking nonsense-mediated mRNA decay results in the reversal of UTRN upregulation, whereas overexpressing DMD does not. Furthermore, overexpressing DMDPTC minigenes in wild-type cells causes UTRN upregulation, as does a wild-type DMD minigene containing a self-cleaving ribozyme. To place these findings in a therapeutic context, we used splice-switching antisense oligonucleotides (ASOs) to induce the skipping of out-of-frame exons of DMD, aiming to introduce PTCs. We found that these ASOs cause UTRN upregulation. In addition, when using an ASO to restore the DMD reading frame in myotubes derived from a DMDΔE52 patient, an actual DMD treatment, UTRN upregulation was reduced. Altogether, these results indicate that an mRNA decay-based mechanism called transcriptional adaptation6-8 plays a key role in UTRN upregulation in DMDPTC patients, and they highlight an unexplored therapeutic application of ASOs, as well as ribozymes, in inducing genetic compensation via transcriptional adaptation.© 2025. The Author(s).FalcucciLaraLDepartment of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.German Centre for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Bad Nauheim, Germany.DooleyChristopher MCMDepartment of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.German Centre for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Bad Nauheim, Germany.AdamoskiDouglasD0000-0001-5062-2586Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.JuanThomasT0000-0002-9654-3717Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.German Centre for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Bad Nauheim, Germany.Excellence Cluster Cardio-Pulmonary Institute, Bad Nauheim, Frankfurt, Giessen, Germany.Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.MartinezJustinJ0009-0001-4454-3168Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.GeorgievaAngelina MAM0000-0002-3215-427XDepartment of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.MamchaouiKamelKSorbonne Université, Inserm, Institut de Myologie, Centre de Recherche en Myologie, Paris, France.CirziCansuCDepartment of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.Excellence Cluster Cardio-Pulmonary Institute, Bad Nauheim, Frankfurt, Giessen, Germany.StainierDidier Y RDYR0000-0002-0382-0026Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany. didier.stainier@mpi-bn.mpg.de.German Centre for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Bad Nauheim, Germany. didier.stainier@mpi-bn.mpg.de.Excellence Cluster Cardio-Pulmonary Institute, Bad Nauheim, Frankfurt, Giessen, Germany. didier.stainier@mpi-bn.mpg.de.eng Max Planck SocietyEuropean Research Council under the European Union’s research and innovation programmesJournal ArticleResearch Support, Non-U.S. Gov't20250212
EnglandNature04104620028-08360Utrophin0Dystrophin0Codon, Nonsense0Oligonucleotides, Antisense0RNA, Messenger0DMD protein, human0UTRN protein, humanIMMuscular Dystrophy, DuchennegeneticstherapymetabolismHumansUtrophingeneticsmetabolismUp-RegulationgeneticsDystrophingeneticsmetabolismExonsgeneticsNonsense Mediated mRNA DecaygeneticsCodon, NonsensegeneticsRNA StabilitygeneticsOligonucleotides, AntisensegeneticsTranscription, GeneticgeneticsRNA, MessengermetabolismgeneticsAlternative SplicinggeneticsAnimalsMuscle Fibers, SkeletalmetabolismReading FramesgeneticsMiceMutationgeneticsCompeting interests: The Max Planck Society filed a patent application for ASOs to trigger TA (listing L.F., C.M.D. and D.Y.R.S. as inventors) and another patent application for minigenes containing self-cleaving ribozymes to trigger TA (listing L.F., T.J. and D.Y.R.S. as inventors). 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