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<p>Duchenne muscular dystrophy (DMD) is an incurable muscle-wasting disorder characterized by chronic membrane damage, inflammation, and progressive fibrosis. Fibrosis in DMD is driven by sustained TGFβ signaling, which promotes extracellular matrix (ECM) accumulation. We previously showed that SETDB1 sustains the TGFβ-induced fibrotic response in DMD myotubes. Here, we further show that SETDB1 modulates the TGFβ-induced secretome, particularly by regulating ECM-related proteins. Comparison of the basal secretome from DMD patient-derived myotubes and healthy controls revealed a distinct disease-specific profile. Integrating both secretome analyses, we identified EMILIN1, an ECM glycoprotein not previously studied in skeletal muscle, as a robust shared candidate; EMILIN1 is enriched in the DMD secretome, further upregulated by TGFβ, and downregulated upon SETDB1 depletion. We confirmed EMILIN1 overexpression in DMD patient muscle biopsies, validating its pathological relevance. Functionally, <i>EMILIN1</i> depletion modulated myogenic differentiation and reduced expression of the fibrotic marker <i>SERPINE1</i>. These findings establish EMILIN1 as a novel secreted regulator of myogenesis and fibrosis, and implicate SETDB1 in shaping the TGFβ-dependent secretome in DMD. Our integrative proteomic approach provides new insights into the molecular drivers of impaired regeneration in DMD and highlights potential therapeutic targets.</p>

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EMILIN1 emerges as a TGFβ/SETDB1-regulated secreted biomarker in Duchenne muscular dystrophy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月9日

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  • Maeva Zamperoni,
  • Laura Muraine,
  • Minh-Y Tran,
  • Alice Granados,
  • Anne Bigot,
  • Valentin Petit,
  • Mona Bensalah,
  • Jessica Ohana,
  • Véronique Legros,
  • Ekaterina Boyarchuk,
  • Johanna Bruce,
  • Guillaume Chevreux,
  • Véronique Joliot,
  • Elisa Negroni,
  • Maryline Moulin,
  • Capucine Trollet,
  • Slimane Ait-Si-Ali

摘要

Duchenne muscular dystrophy (DMD) is an incurable muscle-wasting disorder characterized by chronic membrane damage, inflammation, and progressive fibrosis. Fibrosis in DMD is driven by sustained TGFβ signaling, which promotes extracellular matrix (ECM) accumulation. We previously showed that SETDB1 sustains the TGFβ-induced fibrotic response in DMD myotubes. Here, we further show that SETDB1 modulates the TGFβ-induced secretome, particularly by regulating ECM-related proteins. Comparison of the basal secretome from DMD patient-derived myotubes and healthy controls revealed a distinct disease-specific profile. Integrating both secretome analyses, we identified EMILIN1, an ECM glycoprotein not previously studied in skeletal muscle, as a robust shared candidate; EMILIN1 is enriched in the DMD secretome, further upregulated by TGFβ, and downregulated upon SETDB1 depletion. We confirmed EMILIN1 overexpression in DMD patient muscle biopsies, validating its pathological relevance. Functionally, EMILIN1 depletion modulated myogenic differentiation and reduced expression of the fibrotic marker SERPINE1. These findings establish EMILIN1 as a novel secreted regulator of myogenesis and fibrosis, and implicate SETDB1 in shaping the TGFβ-dependent secretome in DMD. Our integrative proteomic approach provides new insights into the molecular drivers of impaired regeneration in DMD and highlights potential therapeutic targets.