The cGAS–STING pathway contributes to cisplatin-induced skeletal muscle atrophy through altered proteostasis and myogenic signaling

Cisplatin chemotherapy is widely used for cancer treatment but frequently induces skeletal muscle atrophy, which compromises physical function and patient outcomes. The molecular mechanisms underlying this process remain incompletely understood. The cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) signaling pathway, classically involved in innate immune responses, has recently been implicated in cellular stress and tissue dysfunction. Whether cGAS–STING signaling contributes to cisplatin-induced skeletal muscle atrophy remains unclear.

We employed both pharmacological and genetic approaches. Wild-type (WT) mice received a single intraperitoneal injection of the STING agonist DMXAA prior to cisplatin administration. Genetic models included global cGAS and STING knockout mice, as well as skeletal muscle–specific cGAS knockout mice. Cisplatin was administered intraperitoneally (3 mg/kg/day) for four consecutive days. Body weight, skeletal muscle mass, myofiber cross-sectional area (CSA), and fiber diameter were assessed. Molecular and transcriptional analyses were performed using Western blotting, quantitative polymerase chain reaction, and RNA sequencing.

Pretreatment with the STING agonist DMXAA exacerbated cisplatin-induced body weight loss and skeletal muscle atrophy. In contrast, genetic deletion of cGAS or STING attenuated the loss of gastrocnemius and tibialis anterior muscle mass. Skeletal muscle–specific cGAS deficiency preserved muscle weight and myofiber diameter following cisplatin exposure. Although CSA was also assessed, no significant difference was observed between groups. Transcriptomic analysis identified 696 differentially expressed genes upon cGAS deletion, with enrichment in pathways related to inflammatory signaling, proteasome function, and autophagy. Further analyses in skeletal muscle–specific cGAS-deficient mice showed reduced expression of muscle atrophy–associated genes (FBXO32 and Murf1), together with preservation of key myogenic regulators after cisplatin treatment. Consistently, NF-κB signaling and interferon-stimulated gene expression were diminished, accompanied by altered Beclin1 responses and partial attenuation of selected autophagy-related genes.

These findings support a role for cGAS–STING signaling in cisplatin-induced skeletal muscle atrophy, associated with enhanced innate immune and inflammatory signaling, proteolytic and autophagy-related alterations, and impaired myogenic regulation. Targeting the cGAS–STING pathway may represent a potential therapeutic strategy to mitigate chemotherapy-associated skeletal muscle atrophy.