Sugt1 loss in skeletal muscle stem cells impairs muscle regeneration and causes premature muscle aging.

Adult skeletal muscle stem cells (MuSCs) are essential for muscle homeostasis and regeneration. During aging, the number of MuSCs and their regenerative capacity gradually decline but the underlying mechanisms remain elusive. Here, we identify Sugt1 (suppressor of G2 allele of SKP1 homolog), which is a chaperone for kinetochore function during mitosis and is essential for muscle regeneration by regulating MuSC proliferation. Sugt1 expression level is low in quiescent MuSCs but highly induced when the cells become activated and expand as proliferating myoblasts. Inducible inactivation of Sugt1 in MuSCs causes impaired muscle regeneration upon acute injury by impairing MuSC proliferation. Furthermore, loss of Sugt1 leads to cell cycle arrest in the G2/M phase and cellular senescence. Moreover, long-term loss of Sugt1 in MuSCs results in precocious muscle aging by inhibiting MuSC cell proliferation and promoting cellular senescence. Mechanistically, we identify a cytosolic E3 ubiquitin-ligase, Trim21 as a protein interacting partner for Sugt1 in myoblast cells. We further demonstrate that Sugt1 promotes the ubiquitination of p21 via Trim21; and Sugt1 loss causes p21 accumulation to inhibit cell cycle progression and stimulates cellular senescence. Collectively, our findings uncover that Sugt1 is an essential regulator for MuSC regenerative function during muscle regeneration and aging.