Transcription factor activity divergence across muscle atrophy conditions: A comparative analysis of spaceflight,...

Skeletal muscle atrophy arises from heterogeneous insults including spaceflight, aging, and immobilization. Prior studies have catalogued differentially expressed genes (DEGs) in each context, but the transcription factors (TFs) coordinating these programs remain inconsistently characterized across conditions, and gene-level overlap between conditions is small. Three mouse transcriptomic datasets were analyzed: NASA OSD-576 (Rodent Research-23) tibialis anterior muscle from spaceflight versus ground control animals; GSE145480 gastrocnemius muscle from 28-month-old versus 8-month-old mice as a sarcopenia model; and GSE273092 gastrocnemius muscle from mice subjected to ten days of hindlimb unloading versus weight-bearing controls as a disuse atrophy model. For each, gene-level Wald statistics from PyDESeq2 were used to infer TF activity with decoupleR's univariate linear model (ULM) against the CollecTRI mouse regulon (43,226 TF-target interactions, 1,165 TFs). TFs were classified as pan-atrophy, partial, or condition-specific based on |NES| ≥ 1.5 in 3, 2, or 1 conditions. Of 732 TFs scored, 47 (6.4%) were pan-atrophy, 161 (22.0%) partial, and 295 (40.3%) condition-specific. Pearson correlation of TF activity profiles was highest between spaceflight and disuse atrophy (r = 0.4573) and lowest between spaceflight and sarcopenia (r = 0.1459). Pan-atrophy regulators included the glucocorticoid receptor Nr3c1, Foxo1, the chromatin remodeller Smarca4, and the stress regulators Pml and Ing4; Stat1 crossed the threshold but showed a sign-discordant pattern, repressed in spaceflight and disuse but activated in sarcopenia. Spaceflight showed repression of Hsf1/Hsf2/Hsf4 and activation of Hdac7; sarcopenia uniquely activated Spi1, Stat5a, and Irf2; disuse atrophy uniquely activated Mlxipl and Ovol1. This comparative transcriptomic analysis reveals a small but biologically coherent set of pan-atrophy regulators dominated by glucocorticoid and FoxO signaling, alongside a much larger pool of condition-specific regulators encoding the stressor of origin, narrowing the candidate regulator list warranting further investigation for relevance to muscle wasting broadly and to spaceflight specifically.