p21 induces a senescence program and skeletal muscle dysfunction

Area of Science:

• Cellular Biology
• Muscle Physiology
• Aging Research

Background:

• Elevated p21 levels correlate with senescent cell accumulation and skeletal muscle dysfunction in both mice and humans.
• The precise mechanistic role of p21 in driving skeletal muscle pathology remains to be fully elucidated.

Purpose of the Study:

• To investigate whether p21 overexpression is sufficient to induce cellular senescence and pathological features in skeletal muscle.
• To explore the mechanistic contribution of p21 to skeletal muscle dysfunction.

Main Methods:

• Utilized a mouse model with p21 overexpression (p21OE).
• Assessed core properties of cellular senescence, including transcriptomic changes, DNA damage, and mitochondrial function.
• Evaluated the senescence-associated secretory phenotype (SASP).
• Compared pathological features (atrophy, fibrosis) and physical function in p21OE mice versus age-matched controls.

Main Results:

• p21 overexpression induced key features of cellular senescence in skeletal muscle.
• Observed altered transcriptome, DNA damage, and mitochondrial dysfunction in p21OE muscle.
• Confirmed the induction of SASP by p21.
• p21OE mice displayed significant skeletal muscle atrophy, fibrosis, and impaired physical function compared to controls.

Conclusions:

• p21 is sufficient to drive a cellular senescence program in skeletal muscle.
• p21 overexpression directly contributes to skeletal muscle atrophy, fibrosis, and functional decline.
• These findings identify p21 as a novel factor implicated in age-related skeletal muscle loss and dysfunction.