Engineered Muscle Tissue Analysis of Irisin Protection Against Glucocorticoid- and Cancer Cachexia-Induced Muscle Wasting and Cardiotoxicity.

Muscle atrophy, a condition characterized by an imbalance between protein synthesis and degradation, leads to skeletal muscle wasting, exacerbating disease progression and increasing mortality rates. Exercise has been shown to counteract muscle wasting, with myokines-exercise-induced secretome proteins, and among them, irisin is known to mediate systemic benefits such as improved metabolism, reduction of oxidative stress, and promotion of tissue repair in skeletal muscle, thereby mediating beneficial effects of exercise against atrophy. Despite its promising therapeutic potential, the precise functions and signaling pathways of irisin in muscle and other organs remain insufficiently explored owing to the complexity and heterogeneity of in vivo environments. In this study, we present engineered skeletal muscle tissue models as biomimetic platforms to study irisin-mediated therapeutic interventions. Using this platform, we validated the ability of irisin to mitigate dexamethasone (DEX)-induced muscle atrophy by restoring myogenic markers, enhancing AKT-mediated protein synthesis, suppressing ubiquitin-proteasome-driven degradation, and preserving contractile function under catabolic stress. (e.g., irisin pretreatment increased tetanic stress in DEX-treated tissues by ~ 43% vs. DEX alone, Supplementary Information: The online version contains supplementary material available at 10.1007/s13206-026-00268-9.