Abstract

Skeletal muscle atrophy is characterized by diminished muscle mass and function, which can arise from aging, nerve damage, and disease-related secondary atrophy. A central unresolved question is how these diverse stressors trigger common downstream mechanisms to cause sustained muscle deterioration. Here, we confirmed the role of cytosolic double-stranded RNA (dsRNA) in muscle atrophy across multiple murine models (aging, denervation and dexamethasone). Accumulated dsRNA released from damaged mitochondria aberrantly activated the innate immune sensor RIG-I signaling, triggering inflammation and muscle wasting. Moreover, adoptive transfer of mitochondrial dsRNA (mt-dsRNA) into healthy myotubes was sufficient to recapitulate the atrophic phenotype and activate RIG-I signaling. Furthermore, E3 ligase TRIM72 was identified as muscle-specific regulator of RIG-I signaling. TRIM72 attenuates the mt-dsRNA/RIG-I axis through two mechanisms. One is ubiquitinating RIG-I via interaction with its CARD domain to trigger degradation, the other is preserving mitochondria to prevent dsRNA leakage. Consequently, TRIM72 deficiency exacerbated atrophy while supplementation with recombinant TRIM72 (rhT72) improved muscle conditions and suppressed RIG-I signaling in vivo. In a clinic cohort, plasma TRIM72 level declined with muscle atrophy across multiple pathologies and rose with muscle recovery. Overall, our findings revealed mt-dsRNA/RIG-I axis as a key pathogenic pathway in muscle atrophy and identified TRIM72 as a key regulator and potential therapeutic agent.