Santiago Larion Martin, Oguntuyo Kasoorelope, Chin-Young Britney, Laudier Damien, Yu Zhixin, Alves da Silva Pedro Henrique, Fang Fei, Amabile Angelo, Han Woojin M
Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, NY.
Department of Cell, Development, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY.
Cell Mol Bioeng. 2025 Aug 23. doi: 10.1007/s12195-025-00859-w.
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.
W7a-LNP efficacy was assessed and 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. , 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.
W7a-LNP inhibited adipogenesis and increased myofiber size . 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.
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.
肌脂肪变性和肌肉萎缩是慢性损伤、退行性肌病及衰老过程中骨骼肌退变的关键病理特征。虽然重组WNT7A在刺激肌肉肥大和减少脂肪浸润方面显示出前景，但其临床转化受到递送、可扩展性和成本方面挑战的限制。本研究的目的是评估脂质纳米颗粒（LNP）介导的WNT7A mRNA递送（W7a-LNP）作为减轻肌肉退变的替代策略的可行性。
使用原代小鼠成纤维脂肪生成祖细胞（FAPs）、C2C12成肌细胞和肌肉损伤小鼠模型评估W7a-LNP的疗效。在W7a-LNP处理后对FAP脂肪生成和肌纤维大小进行定量。此外，通过肌肉注射将W7a-LNP给予未受伤和甘油损伤的肌肉，并分析其对肌纤维大小和肌肉内脂肪组织（IMAT）形成的影响。
W7a-LNP抑制脂肪生成并增加肌纤维大小。在未受伤的肌肉中，多次注射W7a-LNP可显著增加肌纤维大小而不诱导纤维化，证实其在促进肌肉肥大方面的安全性和有效性。然而，在甘油损伤模型中，损伤后早期递送W7a-LNP治疗对减少IMAT显示出可变的效果，这可能是由于缺乏mRNA摄取和蛋白质产生所需的存活肌纤维。损伤后4天延迟递送显著减少脂肪浸润，支持了时间和靶细胞可用性对治疗效果的重要性。
这些发现提供了概念验证，即W7a-LNP可增强肌纤维肥大并调节脂肪浸润，支持mRNA LNP技术作为对抗肌肉退变的重组蛋白疗法的可扩展和局部替代方法。进一步优化剂量、递送频率和生物分布对于临床转化至关重要。
