Aging concomitantly reduces skeletal muscle proteome plasticity and hypertrophic responses to resistance training in male adults.

Resistance training (RT)-induced hypertrophy is attenuated with aging, albeit the proteomic basis of this attenuation remains unclear. We thus determined whether reduced skeletal muscle proteome plasticity accompanies age-related blunted hypertrophic responses. Seventeen younger (21.9 ± 2.5 years) and 15 older (57.5 ± 6.9 years) untrained males completed 10-12 weeks of RT, and the vastus lateralis (VL) soluble proteome was profiled pre- and post-training using data-independent acquisition mass spectrometry (2106 proteins). Despite similar training volume (p = 0.771), younger adults gained more lean body mass (+2.73 vs. +1.18 kg, p = 0.009) and VL thickness (+0.49 vs. +0.20 cm, p = 0.002) than older adults. Proteome plasticity paralleled this divergence, as RT altered 135 proteins (FDR < 0.05) in younger adults and none in older adults. This attenuation was one of magnitude rather than direction, as 81.5% of the 135 younger-adult proteins shifted concordantly in older adults (ρ = 0.711), and 75 gene sets were enriched with RT in older adults, led by translational machinery (NES up to +2.85). At baseline, 278 proteins differed between age groups (FDR <0.05), and age dominated the co-expression network (Turquoise module AUC = 0.96). In conclusion, the blunted hypertrophic response of older males coincides with a loss of RT-induced proteome plasticity, reflecting a compressed rather than qualitatively altered RT adaptation.