Serum C-terminal agrin fragment as a biomarker of age-related neuromuscular decline in men: influence of physical activity

Aging is accompanied by progressive neuromuscular junction (NMJ) degeneration. The C-terminal agrin fragment (CAF), a circulating product of agrin cleavage, has been proposed as a minimally invasive biomarker of NMJ degradation, but its relationships with neuromuscular and functional characteristics, and the influence of physical activity, remain underexplored. We studied 136 community-dwelling men aged 20-92 years (active, n=87; inactive, n=49). Serum CAF was measured by ELISA. The proportion of NCAM-positive fibers, a marker of myofiber denervation, was assessed in vastus lateralis biopsies (n=127). Neuromuscular outcomes included maximal voluntary isometric contraction (MVIC), lower-limb power, electromechanical delay (EMD), nerve conduction velocities, H/M ratio, central activation ratio, co-activation, and twitch characteristics. Functional capacity was assessed using the 6-minute walk test, alternating step test, Timed Up and Go, sit-to-stand tests, and fast gait speed. Serum CAF increased with age and was positively associated with NCAM-positive fiber proportion. Higher CAF was associated with lower MVIC, lower-limb power and poorer performance on all functional tests. CAF was associated with longer EMD in the overall cohort and in inactive men only, and with a lower H/M ratio in inactive men. No associations were found with nerve conduction velocities, central activation ratio, co-activation, or twitch amplitude. Active men had lower CAF levels than inactive men, particularly after age 70. Serum CAF is associated with age-related declines in neuromuscular and functional capacity and with NCAM-positive fiber prevalence, supporting its utility as an accessible biomarker of NMJ remodeling. Physical activity was associated with a more favorable CAF profile in older men.