TY - GEN A1 - Hüttner, Sören A1 - Henze, Henriette A1 - Elster, Dana A1 - Koch, Philipp A1 - Anderer, Ursula A1 - Eyss, Björn von A1 - Maltzahn, Julia von T1 - A dysfunctional miR-1-TRPS1-MYOG axis drives ERMS by suppressing terminal myogenic differentiation T2 - Molecular Therapy N2 - Rhabdomyosarcoma is the most common pediatric soft tissue tumor, comprising two major subtypes: the PAX3/7-FOXO1 fusion-negative embryonal and the PAX3/7-FOXO1 fusion-positive alveolar subtype. Here, we demonstrate that the expression levels of the transcriptional repressor TRPS1 are specifically enhanced in the embryonal subtype, resulting in impaired terminal myogenic differentiation and tumor growth. During normal myogenesis, expression levels of TRPS1 have to decrease to allow myogenic progression, as demonstrated by overexpression of TRPS1 in myoblasts impairing myotube formation. Consequentially, myogenic differentiation in embryonal rhabdomyosarcoma in vitro as well as in vivo can be achieved by reducing TRPS1 levels. Furthermore, we show that TRPS1 levels in RD cells, the bona fide model cell line for embryonal rhabdomyosarcoma, are regulated by miR-1 and that TRPS1 and MYOD1 share common genomic binding sites. The myogenin (MYOG) promoter is one of the critical targets of TRPS1 and MYOD1; we demonstrate that TRPS1 restricts MYOG expression and thereby inhibits terminal myogenic differentiation. Therefore, reduction of TRPS1 levels in embryonal rhabdomyosarcoma might be a therapeutic approach to drive embryonal rhabdomyosarcoma cells into myogenic differentiation, thereby generating postmitotic myotubes. Y1 - 2023 U6 - https://doi.org/10.1016/j.ymthe.2023.07.003 SN - 1525-0024 SN - 1525-0016 VL - 31 IS - 9 SP - 2612 EP - 2632 ER - TY - GEN A1 - Henze, Henriette A1 - Hüttner, Sören S. A1 - Koch, Philipp A1 - Schüler, Svenja C. A1 - Groth, Marco A1 - von Eyss, Björn A1 - von Maltzahn, Julia T1 - Denervation alters the secretome of myofibers and thereby affects muscle stem cell lineage progression and functionality T2 - npj regenerative medicine N2 - Skeletal muscle function crucially depends on innervation while repair of skeletal muscle relies on resident muscle stem cells (MuSCs). However, it is poorly understood how innervation affects MuSC properties and thereby regeneration of skeletal muscle. Here, we report that loss of innervation causes precocious activation of MuSCs concomitant with the expression of markers of myogenic differentiation. This aberrant activation of MuSCs after loss of innervation is accompanied by profound alterations on the mRNA and protein level. Combination of muscle injury with loss of innervation results in impaired regeneration of skeletal muscle including shifts in myogenic populations concomitant with delayed maturation of regenerating myofibers. We further demonstrate that loss of innervation leads to alterations in myofibers and their secretome, which then affect MuSC behavior. In particular, we identify an increased secretion of Osteopontin and transforming growth factor beta 1 (Tgfb1) by myofibers isolated from mice which had undergone sciatic nerve transection. The altered secretome results in the upregulation of early activating transcription factors, such as Junb , and their target genes in MuSCs. However, the combination of different secreted factors from myofibers after loss of innervation is required to cause the alterations observed in MuSCs after loss of innervation. These data demonstrate that loss of innervation first affects myofibers causing alterations in their secretome which then affect MuSCs underscoring the importance of proper innervation for MuSC functionality and regeneration of skeletal muscle. Y1 - 2024 U6 - https://doi.org/10.1038/s41536-024-00353-3 SN - 2057-3995 VL - 9 IS - 1 SP - 1 EP - 14 PB - Nature Publishing Group UK CY - London ER - TY - GEN A1 - Schurig, Mona A1 - Umeh, Obinna A1 - Henze, Henriette A1 - Jung, Marie Juliane A1 - Gresing, Lennart A1 - Blanchard, Veronique A1 - Maltzahn, Julia von A1 - Hübner, Christian A1 - Franzka, Patricia T1 - Consequences of GMPPB deficiency for neuromuscular development and maintenance T2 - Frontiers in Molecular Neuroscience N2 - Guanosine diphosphate-mannose pyrophosphorylase B (GMPPB) catalyzes the conversion of mannose-1-phosphate and GTP to GDP-mannose, which is required as a mannose donor for the biosynthesis of glycan structures necessary for proper cellular functions. Mutations in GMPPB have been associated with variable neuromuscular disorders such as muscular dystrophy and myasthenic syndromes. Here, we report that GMPPB protein abundance increases during brain and skeletal muscle development, which is accompanied by an increase in overall protein mannosylation. To model the human disorder in mice, we generated heterozygous GMPPB KO mice using CRISPR/Cas9. While we were able to obtain homozygous KO mice from heterozygous matings at the blastocyst stage, homozygous KO embryos were absent beyond embryonic day E8.5, suggesting that the homozygous loss of GMPPB results in early embryonic lethality. Since patients with GMPPB loss-of-function manifest with neuromuscular disorders, we investigated the role of GMPPB in vitro. Thereby, we found that the siRNA-mediated knockdown of Gmppb in either primary myoblasts or the myoblast cell line C2C12 impaired myoblast differentiation and resulted in myotube degeneration. siRNA-mediated knockdown of Gmppb also impaired the neuron-like differentiation of N2A cells. Taken together, our data highlight the essential role of GMPPB during development and differentiation, especially in myogenic and neuronal cell types. Y1 - 2024 U6 - https://doi.org/10.3389/fnmol.2024.1356326 SN - 1662-5099 VL - 17 ER - TY - GEN A1 - Schmidt, Manuel A1 - Maltzahn, Julia von A1 - Poser, Christine A1 - Janster, Christina T1 - The hairpin region of WNT7A is sufficient for binding to the Frizzled7 receptor and to elicit signaling in myogenic cells T2 - Computational and Structural Biotechnology Journal Y1 - 2022 U6 - https://doi.org/10.1016/j.csbj.2022.10.047 SN - 2001-0370 VL - 20 SP - 6348 EP - 6359 ER - TY - GEN A1 - Maltzahn, Julia von T1 - TRPS1 drives tumor growth in embryonal rhabdomyosarcoma through impairing terminal myogenic differentiation T2 - Embo Workshop: Muscle formation, maintenance, regeneration and pathology Y1 - 2022 UR - https://zenodo.org/records/10673901 U6 - https://doi.org/10.5281/zenodo.10673901 ER - TY - GEN A1 - Majchrzak, Karolina A1 - Hentschel, Erik A1 - Hönzke, Katja A1 - Geithe, Christiane A1 - Maltzahn, Julia von T1 - We need to talk—how muscle stem cells communicate T2 - Frontiers in Cell and Developmental Biology N2 - Skeletal muscle is one of the tissues with the highest ability to regenerate, a finely controlled process which is critically depending on muscle stem cells. Muscle stem cell functionality depends on intrinsic signaling pathways and interaction with their immediate niche. Upon injury quiescent muscle stem cells get activated, proliferate and fuse to form new myofibers, a process involving the interaction of multiple cell types in regenerating skeletal muscle. Receptors in muscle stem cells receive the respective signals through direct cell-cell interaction, signaling via secreted factors or cell-matrix interactions thereby regulating responses of muscle stem cells to external stimuli. Here, we discuss how muscle stem cells interact with their immediate niche focusing on how this controls their quiescence, activation and self-renewal and how these processes are altered in age and disease. KW - muscle stem cell KW - satellite cell KW - skeletal muscle KW - regeneration KW - niche KW - receptor KW - aging KW - rhabdomyosarcoma Y1 - 2024 U6 - https://doi.org/10.3389/fcell.2024.1378548 SN - 2296-634X VL - 12 PB - Frontiers Media S.A. ER - TY - GEN A1 - Maltzahn, Julia von T1 - Muscle stem cells in age and disease T2 - ERIBA : University Medical Center Groningen (UMCG), The Netherlands, 28 – 30 September 2023 Y1 - 2023 UR - https://www.g-jam.eu/_files/ugd/0ef1c8_5f942ee70fc1464ea5d5fec147e9c2b7.pdf U6 - https://doi.org/10.5281/zenodo.10673943 SP - 34 ER - TY - GEN A1 - Lyu, Yu-Xuan A1 - Fu, Qiang A1 - Wilczok, Dominika A1 - Ying, Kejun A1 - King, Aaron A1 - Antebi, Adam A1 - Vojta, Aleksandar A1 - Stolzing, Alexandra A1 - Moskalev, Alexey A1 - Georgievskaya, Anastasia A1 - Maier, Andrea B. A1 - Olsen, Andrea A1 - Groth, Anja A1 - Simon, Anna Katharina A1 - Brunet, Anne A1 - Jamil, Aisyah A1 - Kulaga, Anton A1 - Bhatti, Asif A1 - Yaden, Benjamin A1 - Pedersen, Bente Klarlund A1 - Schumacher, Björn A1 - Djordjevic, Boris A1 - Kennedy, Brian A1 - Chen, Chieh A1 - Huang, Christine Yuan A1 - Correll, Christoph U. A1 - Murphy, Coleen T. A1 - Ewald, Collin Y. A1 - Chen, Danica A1 - Valenzano, Dario Riccardo A1 - Sołdacki, Dariusz A1 - Erritzoe, David A1 - Meyer, David A1 - Sinclair, David A. A1 - Chini, Eduardo Nunes A1 - Teeling, Emma C. A1 - Morgen, Eric A1 - Verdin, Eric A1 - Vernet, Erik A1 - Pinilla, Estefano A1 - Fang, Evandro F. A1 - Bischof, Evelyne A1 - Mercken, Evi M. A1 - Finger, Fabian A1 - Kuipers, Folkert A1 - Pun, Frank W. A1 - Gyülveszi, Gabor A1 - Civiletto, Gabriele A1 - Zmudze, Garri A1 - Blander, Gil A1 - Pincus, Harold A. A1 - McClure, Joshua A1 - Kirkland, James L. A1 - Peyer, James A1 - Justice, Jamie N. A1 - Vijg, Jan A1 - Gruhn, Jennifer R. A1 - McLaughlin, Jerry A1 - Mannick, Joan A1 - Passos, João A1 - Baur, Joseph A. A1 - Betts-LaCroix, Joe A1 - Sedivy, John M. A1 - Speakman, John R. A1 - Shlain, Jordan A1 - Maltzahn, Julia von A1 - Andreasson, Katrin I. A1 - Moody, Kelsey A1 - Palikaras, Konstantinos A1 - Fortney, Kristen A1 - Niedernhofer, Laura J. A1 - Rasmussen, Lene Juel A1 - Veenhoff, Liesbeth M. A1 - Melton, Lisa A1 - Ferrucci, Luigi A1 - Quarta, Marco A1 - Koval, Maria A1 - Marinova, Maria A1 - Hamalainen, Mark A1 - Unfried, Maximilian A1 - Ringel, Michael S. A1 - Filipovic, Milos A1 - Topors, Mourad A1 - Mitin, Natalia A1 - Roy, Nawal A1 - Pintar, Nika A1 - Barzilai, Nir A1 - Binetti, Paolo A1 - Singh, Parminder A1 - Kohlhaas, Paul A1 - Robbins, Paul D. A1 - Rubin, Paul A1 - Fedichev, Peter O. A1 - Kamya, Petrina A1 - Muñoz-Canoves, Pura A1 - de Cabo, Rafael A1 - Faragher, Richard G. A. A1 - Konrad, Rob A1 - Ripa, Roberto A1 - Mansukhani, Robin A1 - Büttner, Sabrina A1 - Wickström, Sara A. A1 - Brunemeier, Sebastian A1 - Jakimov, Sergey A1 - Luo, Shan A1 - Rosenzweig-Lipson, Sharon A1 - Tsai, Shih-Yin A1 - Dimmeler, Stefanie A1 - Rando, Thomas A. A1 - Peterson, Tim R. A1 - Woods, Tina A1 - Wyss-Coray, Tony A1 - Finkel, Toren A1 - Strauss, Tzipora A1 - Gladyshev, Vadim N. A1 - Longo, Valter D. A1 - Dwaraka, Varun B. A1 - Gorbunova, Vera A1 - Acosta-Rodríguez, Victoria A. A1 - Sorrentino, Vincenzo A1 - Sebastiano, Vittorio A1 - Li, Wenbin A1 - Suh, Yousin A1 - Zhavoronkov, Alex A1 - Scheibye-Knudsen, Morten A1 - Bakula, Daniela T1 - Longevity biotechnology: bridging AI, biomarkers, geroscience and clinical applications for healthy longevity T2 - Aging Y1 - 2024 U6 - https://doi.org/10.18632/aging.206135 SN - 1945-4589 VL - 16 IS - 20 SP - 12955 EP - 12976 PB - Impact Journals, LLC ER - TY - CHAP A1 - Maltzahn, Julia von T1 - Analyzing muscle stem cell function Ex Vivo T2 - Methods in Molecular Biology Y1 - 2025 U6 - https://doi.org/10.1007/7651_2024_589 SP - 1 EP - 10 PB - Springer CY - New York ER - TY - GEN A1 - Sahinyan, Korin A1 - Blackburn, Darren M. A1 - Simon, Marie-Michelle A1 - Lazure, Felicia A1 - Kwan, Tony A1 - Wilson, David H. A1 - Vahidyeganeh, Maryam A1 - Alsadi, Nawal A1 - Maltzahn, Julia von A1 - Yamada, Yasuhiro A1 - Jahani-Asl, Arezu A1 - Bourque, Guillaume A1 - Rudnicki, Michael A. A1 - Soleimani, Vahab D. T1 - REST/NRSF Preserves muscle stem cell identity by repressing alternate cell fate T2 - Nature communications N2 - Cell fate and identity require timely activation of lineage-specific and concomitant repression of alternate-lineage genes. How this process is epigenetically encoded remains largely unknown. In skeletal muscle stem cells, the myogenic regulatory factors are well-established drivers of muscle gene activation but less is known about how non-muscle gene repression is achieved. Here, we show that the master epigenetic regulator, Repressor Element 1-Silencing Transcription factor (REST), also known as Neuron-Restrictive Silencer Factor (NRSF), is a key regulator of this process. We show that many non-lineage genes retain permissive chromatin state but are actively repressed by REST. Loss of functional REST in muscle stem cells and progenitors disrupts muscle specific epigenetic and transcriptional signatures, impairs differentiation, and triggers apoptosis in progenitor cells, leading to depletion of the stem cell pool. Consequently, REST-deficient skeletal muscle exhibits impaired regeneration and reduced myofiber growth postnatally. Collectively, our data suggests that REST plays a key role in safeguarding muscle stem cell identity by repressing multiple non-muscle lineage and developmentally regulated genes in adult mice. Y1 - 2025 U6 - https://doi.org/10.1038/s41467-025-62758-y VL - 16 SP - 1 EP - 22 PB - Springer Nature CY - [London] ER -