Increased TWEAK and decreased MyoG expression in age-related impairment of muscle regeneration and H2O2-induced senescence-associated changes in C2C12 cells.

Sarcopenia is characterized by the progressive loss of skeletal muscle mass and strength, accompanied by impaired regenerative capacity. This study examined age-related changes in skeletal muscle regeneration and the associated expression of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and myogenin (MyoG). Male C57BL/6 mice aged 3, 13, and 23 months were subjected to barium chloride (BaCl2)-induced tibialis anterior muscle injury. In parallel, C2C12 cells were exposed to repeated low-dose hydrogen peroxide (H2O2) to induce senescence-associated changes under oxidative stress, and the effect of the TWEAK inhibitor L524 was evaluated. Muscle mass and grip strength showed age-dependent declines. Following BaCl2 injury, MyoD expression was induced similarly across age groups, whereas MyoG and embryonic myosin heavy chain expression significantly decreased with advancing age. TWEAK expression increased in injured muscle with age, while p-4E-BP1 showed no clear age-dependent change. In C2C12 cells, repeated H2O2 exposure at 100 μM, which maintained cell viability above 90%, induced senescence-associated changes, reduced myotube formation, increased TWEAK expression, and decreased MyoG expression, whereas treatment with the TWEAK inhibitor L524 attenuated the H2O2-associated reduction in MyoG expression. Collectively, these findings suggest that TWEAK signaling may be associated with oxidative stress and age-related impairments in muscle regeneration.