WNT7A mRNA Lipid Nanoparticles Promote Muscle Hypertrophy and Reduce Fatty Infiltration.

PURPOSE: Myosteatosis and muscle atrophy are key pathological features of skeletal muscle degeneration in chronic injuries, degenerative myopathies, and aging. While recombinant WNT7A has shown promise in stimulating muscle hypertrophy and reducing fatty infiltration, its clinical translation is limited by challenges in delivery, scalability, and cost. The objective of this study was to evaluate the feasibility of lipid nanoparticle (LNP)-mediated mRNA delivery of WNT7A (W7a-LNP) as an alternative strategy for mitigating muscle degeneration. METHODS: W7a-LNP efficacy was assessed in vitro and in vivo using primary murine fibro-adipogenic progenitors (FAPs), C2C12 myoblasts, and mouse models of muscle injury. FAP adipogenesis and myofiber size were quantified following W7a-LNP treatment. In vivo, W7a-LNP was administered via intramuscular injection in uninjured and glycerol-injured muscles, and its effects on myofiber size and intramuscular adipose tissue (IMAT) formation were analyzed. RESULTS: W7a-LNP inhibited adipogenesis and increased myofiber size in vitro. In uninjured muscle, multiple W7a-LNP injections significantly increased myofiber size without inducing fibrosis, confirming its safety and efficacy in promoting muscle hypertrophy. However, in the glycerol injury model, W7a-LNP treatment showed variable effects on IMAT reduction when delivered early post-injury, likely due to the absence of viable myofibers needed for mRNA uptake and protein production. Delayed delivery at 4 days post-injury significantly reduced fatty infiltration, supporting the importance of timing and target cell availability for therapeutic efficacy. CONCLUSIONS: These findings provide proof-of-concept that W7a-LNP enhances myofiber hypertrophy and modulates fatty infiltration, supporting mRNA LNP technology as a scalable and localized alternative to recombinant protein therapy for combating muscle degeneration. Further optimization of dose, delivery frequency, and biodistribution will be critical for clinical translation.