Loss of TDP-43 drives premature aging and impairs skeletal muscle stem cell pool restoration

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Abstract
TAR DNA-binding protein 43 (TDP-43) dysfunction is a hallmark of amyotrophic lateral sclerosis (ALS) and related disorders, yet its role in skeletal muscle stem cells, the satellite cells (SC), remains incompletely understood. Here, we investigated ALS-associated gain- and loss-of-function TDP-43 mutations together with inducible SC-specific TDP-43 deletion. While TDP-43 Q331K and heterozygous TDP-43 F210I mice displayed normal muscle homeostasis, SC abundance, and regenerative capacity, complete TDP-43 loss caused a marked reduction of the SC pool, particularly in females, and shifted SCs from a CD34 high stem-like state toward a CD34 low primed population. TDP-43-deficient SCs failed to clonally expand, proliferate, and differentiate, resulting in severe regenerative failure following muscle injury. Notably, the SC pool failed to recover after injury and was nearly depleted 30 days post-injury, accompanied by muscle loss, fibrosis and fat infiltration. Transcriptomic analyses revealed activation of stress and aging-associated programs in uninjured TDP-43-deficient SCs, indicating the premature acquisition of an aging-like state. Consistently, chronological aging further exacerbated SC depletion, establishing TDP-43 as a critical regulator of SC stemness, regeneration, and resistance to age-related decline.
Funding Information
  • Instituto de Salud Carlos III (PI19/00175)
  • Instituto de Salud Carlos III (PI22/00433)
  • Instituto de Salud Carlos III (PMPPER24/00017)
  • Instituto de Salud Carlos III (FORT23/00026)
  • Centro de Investigación Biomédica en Red (CB06/05/1126)
  • Ministerio de Ciencia, Innovación y Universidades (CNS2024-154512)
  • Gobierno Vasco, Departamento de Educación (NEURODEGENPROT)
  • Gobierno Vasco, Departamento de Educación (NEUROMOTORTHERAPY)
  • Gobierno Vasco, Departamento de Educación (PRE_2019_1_0339)
  • Gobierno Vasco, Departamento de Educación (PRE_2020_1_0119)
  • Gobierno Vasco, Departamento de Educación (PRE_2022_1_0212)
  • Gobierno Vasco, Departamento de Educación (PRE_2023_1_0273)
  • Gobierno Vasco, Departamento de Salud (2020111032)
  • Gobierno Vasco, Departamento de Salud (2023111035)
  • Gobierno Vasco, Departamento de Salud (2023333042)
  • Gobierno Vasco, Departamento de Salud (2024333017)
  • Gobierno Vasco, Departamento de Salud (2025333009)
  • Gobierno Vasco, Departamento de Salud (2025333010)
  • Diputación Foral de Gipuzkoa (2020-CIEN-000057–01)
  • Diputación Foral de Gipuzkoa (2021-CIEN-000020–01)
  • Diputación Foral de Gipuzkoa (2019-FELL-000010–01)
  • Diputación Foral de Gipuzkoa (2020-FELL-000016–02-01)
  • Diputación Foral de Gipuzkoa (2021-FELL-000013–02-01)
  • European Union NextGenerationEU (CERTERA-CERT22/00032)

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