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TDP-43 is required to build and maintain sarcomeres

Gay, H.;Ewachiw, T.;Dhar, S.;Stowell, M.;Olwin, B.

2026-06-16 Cell Biology
10.64898/2026.06.16.732601 bioRxiv
Show abstract

Skeletal muscle contractile units or sarcomeres require constant maintenance as they are subjected to continuous chemical and mechanical stress. When sarcomere maintenance is disrupted, as occurs in progressive neuromuscular diseases, muscle progressively atrophies, reducing muscle strength and motor control. Transient cytoplasmic ribonucleoprotein aggregates comprised of TDP-43 bound to mRNAs encoding sarcomeric structural proteins (myo-granules) are implicated in building muscle. Ablating TDP-43 in differentiated skeletal muscle causes phenotypes remarkably similar to those of progressive neuromuscular diseases, including muscle atrophy, loss of muscle mass, and aberrantly organized sarcomeres. When injured, differentiated muscle lacking TDP-43 is incapable of repair, failing to build sarcomeres, severely disrupting muscle morphology with fibrotic tissue replacing muscle tissue. TDP-43 is thus required to build and maintain sarcomeres, likely protecting and transporting mRNAs encoding sarcomeric structural proteins in myo-granules.

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