Research Square · Oct 21, 2026
Sex-specific alterations in muscle health and related protein and amino acid kinetics in different stages of frailty
By Kang MC, Deutz NE, Ruebush LE et al.
Presence of frailty in older adults is accompanied by declined muscle and bone health, and metabolic disturbances. Little is known about sex-specific changes in protein and amino acid kinetics along the frailty trajectory. We investigated whether older adults at different stages of frailty (non-frailty, pre-frailty, and frailty) exhibited a distinct functional and metabolic phenotype, influenced by biological sex, and the potential of net protein breakdown as a functional biomarker of frailty. In 208 older adults, body composition and bone density (by DXA), skeletal muscle strength (by dynamometry), and functional capacity (by 6-minute walk test (6MWT)) were measured. In the fasted state, a pulse of a stable isotope tracer solution, containing multiple labeled amino acids, was administered. Plasma tracer enrichments were analyzed by LC-MS/MS to measure protein amino acid kinetics, and net protein breakdown as a global marker of health. In the whole group, handgrip strength and 6MWT distance (P < 0.05) were lower in the pre-frail and frail than in the non-frail. Bone density and leg muscle strength were lowest in the frail. A decrease in leg muscle strength was present in males only (P < 0.001), but muscle and bone loss in females only (P < 0.03). Frailty severity was associated with lower whole-body and net protein breakdown in females (r: -0.29, -0.27, P < 0.007) and a trend toward increased myofibrillar protein breakdown in males (r: 0.22, P = 0.06). Decreased net protein breakdown was further associated with lower protein intake and age in both sexes (r: -0.29, -0.27, P < 0.05) and worse 6MWT performance in females (r: 0.25, P = 0.016). Our findings indicate that the trajectory of frailty is characterized by early functional decline (independent of sex) and disturbances in protein metabolism, featuring lower whole-body and net protein breakdown (particularly in females) and increased myofibrillar protein breakdown (particularly in males), while lean mass and bone density are preserved in males but reduced in females. Sex-specific nutritional and therapeutic approaches therefore need to be considered to optimize muscle and bone health, personalized along the frailty trajectory. The strong association between reduced net protein breakdown and markers of poor functional outcomes suggests a potential role of net protein breakdown as a functional biomarker of frailty.