2-Amino-5-hydroxyhexanoic acid mitigates diabetes-induced skeletal muscle atrophy by preserving protein homeostasis.

2-Amino-5-hydroxy-hexanoic acid (2-AHA), an unusual amino acid isolated from Crotalaria juncea seeds, has been reported to exhibit antioxidant and antidyslipidemic activities. However, its role in maintaining skeletal muscle integrity under diabetic condition remains unexplored. The present study aimed to investigate the protective effects of 2-AHA against diabetes-induced skeletal muscle atrophy using in vitro (L6 myotubes) and in vivo (streptozotocin-induced diabetic rats) models. In L6 myotubes, 2-AHA treatment attenuated high glucose-induced atrophy features by suppressing muscle atrophy markers, increasing myotube diameter, surface area, and myosin heavy chain (MHC) expression, and inhibiting ubiquitin-proteasome-mediated protein degradation. In diabetic rats, 2-AHA administration improved body weight, lean mass, and muscle cross-sectional area, while enhancing grip strength and rotarod performance. Mechanistically, 2-AHA prevented muscle loss by inhibiting ubiquitin-proteasome- and autophagy-mediated protein degradation, concomitant with activation of AKT-mTOR pathway. Findings underscore the protective effects of 2-AHA against diabetes-induced skeletal muscle atrophy via regulating protein synthesis and protein degradation, and reveal its therapeutic implication to safeguard diabetes-associated skeletal muscle atrophy.