AUF1 therapy blocks atrophy, promotes regeneration, re-innervation, and strength for severe muscle injury.

There are currently no approved therapeutic interventions to promote skeletal muscle regeneration following a severe muscle injury, among the most common of debilitating injuries. We developed a novel therapeutic approach, gene or mRNA delivery encoding RNA binding protein AUF1, which orchestrates the end-to-end process of myogenesis, for severe muscle injury. AUF1 supplementation significantly prevents muscle atrophy after severe injury while promoting rapid and complete functional muscle regeneration, and re-innervation by coordinating the stability and translation of key myogenic mRNAs. In preclinical mouse models of skeletal muscle injury, prophylactic systemic administration of muscle-specific AAV8 AUF1 or intramuscular administration of AAV8 AUF1, as well as LNP AUF1 mRNA 24 h after injury, were highly effective in blocking muscle atrophy and accelerating muscle regeneration. Histologic, ultrastructural, and biochemical analyses show that AUF1 supplementation strongly reduces muscle atrophy and accelerates muscle regeneration and re-innervation. Animals receiving AUF1 therapy following muscle injury preserve near-normal muscle strength and function, whereas control animals demonstrate a significant, persistent decline in strength. These findings identify AUF1 therapy as a potential new approach to accelerate muscle recovery and repair and reduce atrophy following injury.