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ResearchIn-Press PreviewCell biologyMuscle biology Open Access | 10.1172/JCI207716

Cellular senescence mediates facioscapulohumeral muscular dystrophy

Usuk Jung,1 Erdong Wei,1 Ana Mitanoska,1 Philipp Heher,2 Kenric Chen,1 Haseeb Ahsan,1 Xu Zhang,3 Giorgio Tasca,2 Paul D. Robbins,5 Nathan K. LeBrasseur,3 Michael Kyba,1 and Darko Bosnakovski1

1Department of Pediatrics and Lillehei Heart Institute, University of Minnesota, Minneapolis, United States of America

2John Walton Muscular Dystrophy Research Centre, NIHR Newcastle Biomedical R, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom

3Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, United States of America

4John Walton Muscular Dystrophy Research Centre, NIHR Newcastle Biomedical R, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle Upon Tyne, United Kingdom

5Masonic Institute on the Biology of Aging and Metabolism and Department of , University of Minnesota, Minneapolis, United States of America

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1Department of Pediatrics and Lillehei Heart Institute, University of Minnesota, Minneapolis, United States of America

2John Walton Muscular Dystrophy Research Centre, NIHR Newcastle Biomedical R, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom

3Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, United States of America

4John Walton Muscular Dystrophy Research Centre, NIHR Newcastle Biomedical R, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle Upon Tyne, United Kingdom

5Masonic Institute on the Biology of Aging and Metabolism and Department of , University of Minnesota, Minneapolis, United States of America

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1Department of Pediatrics and Lillehei Heart Institute, University of Minnesota, Minneapolis, United States of America

2John Walton Muscular Dystrophy Research Centre, NIHR Newcastle Biomedical R, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom

3Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, United States of America

4John Walton Muscular Dystrophy Research Centre, NIHR Newcastle Biomedical R, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle Upon Tyne, United Kingdom

5Masonic Institute on the Biology of Aging and Metabolism and Department of , University of Minnesota, Minneapolis, United States of America

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1Department of Pediatrics and Lillehei Heart Institute, University of Minnesota, Minneapolis, United States of America

2John Walton Muscular Dystrophy Research Centre, NIHR Newcastle Biomedical R, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom

3Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, United States of America

4John Walton Muscular Dystrophy Research Centre, NIHR Newcastle Biomedical R, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle Upon Tyne, United Kingdom

5Masonic Institute on the Biology of Aging and Metabolism and Department of , University of Minnesota, Minneapolis, United States of America

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1Department of Pediatrics and Lillehei Heart Institute, University of Minnesota, Minneapolis, United States of America

2John Walton Muscular Dystrophy Research Centre, NIHR Newcastle Biomedical R, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom

3Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, United States of America

4John Walton Muscular Dystrophy Research Centre, NIHR Newcastle Biomedical R, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle Upon Tyne, United Kingdom

5Masonic Institute on the Biology of Aging and Metabolism and Department of , University of Minnesota, Minneapolis, United States of America

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1Department of Pediatrics and Lillehei Heart Institute, University of Minnesota, Minneapolis, United States of America

2John Walton Muscular Dystrophy Research Centre, NIHR Newcastle Biomedical R, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom

3Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, United States of America

4John Walton Muscular Dystrophy Research Centre, NIHR Newcastle Biomedical R, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle Upon Tyne, United Kingdom

5Masonic Institute on the Biology of Aging and Metabolism and Department of , University of Minnesota, Minneapolis, United States of America

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1Department of Pediatrics and Lillehei Heart Institute, University of Minnesota, Minneapolis, United States of America

2John Walton Muscular Dystrophy Research Centre, NIHR Newcastle Biomedical R, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom

3Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, United States of America

4John Walton Muscular Dystrophy Research Centre, NIHR Newcastle Biomedical R, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle Upon Tyne, United Kingdom

5Masonic Institute on the Biology of Aging and Metabolism and Department of , University of Minnesota, Minneapolis, United States of America

Find articles by Zhang, X. in: PubMed | Google Scholar |

1Department of Pediatrics and Lillehei Heart Institute, University of Minnesota, Minneapolis, United States of America

2John Walton Muscular Dystrophy Research Centre, NIHR Newcastle Biomedical R, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom

3Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, United States of America

4John Walton Muscular Dystrophy Research Centre, NIHR Newcastle Biomedical R, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle Upon Tyne, United Kingdom

5Masonic Institute on the Biology of Aging and Metabolism and Department of , University of Minnesota, Minneapolis, United States of America

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1Department of Pediatrics and Lillehei Heart Institute, University of Minnesota, Minneapolis, United States of America

2John Walton Muscular Dystrophy Research Centre, NIHR Newcastle Biomedical R, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom

3Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, United States of America

4John Walton Muscular Dystrophy Research Centre, NIHR Newcastle Biomedical R, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle Upon Tyne, United Kingdom

5Masonic Institute on the Biology of Aging and Metabolism and Department of , University of Minnesota, Minneapolis, United States of America

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1Department of Pediatrics and Lillehei Heart Institute, University of Minnesota, Minneapolis, United States of America

2John Walton Muscular Dystrophy Research Centre, NIHR Newcastle Biomedical R, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom

3Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, United States of America

4John Walton Muscular Dystrophy Research Centre, NIHR Newcastle Biomedical R, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle Upon Tyne, United Kingdom

5Masonic Institute on the Biology of Aging and Metabolism and Department of , University of Minnesota, Minneapolis, United States of America

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1Department of Pediatrics and Lillehei Heart Institute, University of Minnesota, Minneapolis, United States of America

2John Walton Muscular Dystrophy Research Centre, NIHR Newcastle Biomedical R, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom

3Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, United States of America

4John Walton Muscular Dystrophy Research Centre, NIHR Newcastle Biomedical R, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle Upon Tyne, United Kingdom

5Masonic Institute on the Biology of Aging and Metabolism and Department of , University of Minnesota, Minneapolis, United States of America

Find articles by Kyba, M. in: PubMed | Google Scholar |

1Department of Pediatrics and Lillehei Heart Institute, University of Minnesota, Minneapolis, United States of America

2John Walton Muscular Dystrophy Research Centre, NIHR Newcastle Biomedical R, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom

3Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, United States of America

4John Walton Muscular Dystrophy Research Centre, NIHR Newcastle Biomedical R, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle Upon Tyne, United Kingdom

5Masonic Institute on the Biology of Aging and Metabolism and Department of , University of Minnesota, Minneapolis, United States of America

Find articles by Bosnakovski, D. in: PubMed | Google Scholar |

Published November 5, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI207716.
Copyright © 2026, Jung et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published November 5, 2026 - Version history
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Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is driven by aberrant expression of the early embryonic transcription factor Double Homeobox 4 (DUX4), yet the mechanisms linking low, sporadic DUX4 activity to progressive muscle degeneration remain unclear. Here, we identify cellular senescence as a central and early mechanism in FSHD pathogenesis. Analysis of patient muscle transcriptomes revealed strong enrichment of senescence and senescence-associated secretory phenotype (SASP) programs that correlated with DUX4 activity, clinical severity, and histopathological changes. Notably, these signatures were detectable even in STIR-negative muscles, defining a prodystrophic state characterized by early molecular alterations preceding overt MRI-detectable inflammation and highlighting their potential utility as early biomarkers of disease activity. Using an FSHD mouse model, we show that DUX4-induced muscle injury rapidly triggers senescence, which then progressively expands. Fibroadipogenic progenitors and macrophages emerged as the principal senescent populations and key sources of pro-inflammatory and profibrotic SASP signals. Importantly, senescence was therapeutically modifiable. Treatment with the nucleoside reverse transcriptase inhibitor lamivudine (3TC), which inhibits LINE-1 reverse transcriptase activity, significantly reduced senescence, inflammation, and fibrosis while promoting muscle regeneration. These findings identify cellular senescence as a tractable driver of FSHD and warrant senotherapeutic strategies, particularly lamivudine, for clinical intervention in FSHD.

Graphical Abstract
graphical abstract
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