Sirtuin 3 modulation by high phosphates: a potential mechanism in muscle aging and sarcopenia

Objectives: To investigate the role of elevated phosphate levels in muscle aging, and to elucidate the underlying molecular mechanisms by which high phosphate conditions regulate muscle aging and explore the potential therapeutic role of SIRT3 activation.

Methods: Young (5-month-old) and aged (24-month-old) C57BL/6 mice were compared in terms of body weight, muscle strength, and serum sodium levels. Additionally, C2C12 myoblasts were exposed to 20 mM β-glycerophosphate (BGP) to simulate high phosphate conditions. Cellular senescence was assessed using senescence-associated β-galactosidase (SA-β-GAL) staining and Western blot analysis (P53, p62, and P21). The role of SIRT3 in muscle cell senescence was further investigated by treating C2C12 cells with the SIRT3 Activator 2-APQC.

Results: Aged mice exhibited significantly higher body weight, reduced grip strength, and elevated serum sodium levels compared to young mice, indicating muscle aging. BGP treatment in C2C12 cells induced cellular senescence, as evidenced by elevated SA-β-GAL activity and upregulation of senescence markers P53, p62, and P21. Furthermore, high phosphate levels impaired cell migration and differentiation. Activation of SIRT3 by 2-APQC alleviated these effects, restoring autophagic activity and reversing muscle cell dysfunction.

Conclusions: Elevated serum sodium and phosphate levels are associated with muscle aging in mice. High phosphate induces cellular senescence and impairs muscle function, while SIRT3 activation mitigates these effects, highlighting its potential as a therapeutic target for sarcopenia. Dietary phosphate restriction and activation of SIRT3 may represent effective strategies for combating age-related muscle degeneration.

Muscle aging; SIRT3; high phosphate; muscle function; sarcopenia; senescence-associated β-galactosidase.