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

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.