Hypoxia-induced GRP78 activation disrupts the Fndc5/Irisin axis to accelerate skeletal muscle atrophy.

Hypoxia is a potent inducer of skeletal muscle atrophy; however, the underlying molecular mechanisms remain incompletely defined. Irisin, a myokine derived from Fndc5, plays a critical role in maintaining muscle mass and function, while endoplasmic reticulum (ER) stress has been implicated in muscle degeneration. Here, we investigated the interplay between hypoxia-induced ER stress and irisin regulation in skeletal muscle. Transcriptomic analyses and weighted gene co-expression network analysis (WGCNA) identified Fndc5 and Hspa5 (encoding GRP78) as key genes within hypoxia-related modules, displaying a strong negative correlation. In vivo, mice exposed to hypoxia showed reduced Fndc5/irisin expression accompanied by significant GRP78 upregulation. In vitro, chemical hypoxia and pharmacological induction of GRP78 by HA15 consistently suppressed Fndc5/irisin levels and impaired C2C12 myotube formation. Gene-miRNA network analysis suggested a shared post-transcriptional link between HSPA5-centered ER stress and FNDC5-associated atrophy programs under hypoxia, with miR-34a-5p as a candidate regulator. Collectively, these findings demonstrate that GRP78-driven ER stress under hypoxic conditions disrupts irisin production, thereby accelerating skeletal muscle atrophy. This work highlights a mechanistic axis linking ER stress to irisin deficiency in hypoxia-induced muscle wasting and provides new insights into potential therapeutic targets.