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

IF 5 4区医学 Q3 BIOPHYSICS

Cellular and molecular bioengineering Pub Date : 2025-08-23 DOI:10.1007/s12195-025-00859-w

Larion Martin Santiago, Kasoorelope Oguntuyo, Britney Chin-Young, Damien Laudier, Zhixin Yu, Pedro Henrique Alves da Silva, Fei Fang, Angelo Amabile, Woojin M Han

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引用次数: 0

Abstract

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.

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WNT7A mRNA脂质纳米颗粒促进肌肉肥大和减少脂肪浸润。

目的：骨骼肌骨化病和肌肉萎缩是慢性损伤、退行性肌病和衰老中骨骼肌变性的关键病理特征。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的挑战。本研究的目的是评估脂质纳米颗粒（LNP）介导的mRNA递送WNT7A （W7a-LNP）作为缓解肌肉变性的替代策略的可行性。方法：采用小鼠原代纤维脂肪生成祖细胞（FAPs）、C2C12成肌细胞和小鼠肌肉损伤模型，在体外和体内评价W7a-LNP的疗效。W7a-LNP处理后，定量测定FAP脂肪生成和肌纤维大小。在体内，分别对未损伤和甘油损伤的肌肉进行肌内注射，分析W7a-LNP对肌纤维大小和肌内脂肪组织（IMAT）形成的影响。结果：W7a-LNP抑制体外脂肪生成，增加肌纤维大小。在未损伤肌肉中，多次注射W7a-LNP可显著增加肌纤维大小，但未引起纤维化，证实了其促进肌肉肥大的安全性和有效性。然而，在甘油损伤模型中，损伤后早期给予W7a-LNP治疗对IMAT降低的影响不同，这可能是由于缺乏mRNA摄取和蛋白质产生所需的活肌纤维。损伤后4天延迟分娩可显著减少脂肪浸润，支持时间和靶细胞可用性对治疗效果的重要性。结论：这些发现提供了W7a-LNP增强肌纤维肥大和调节脂肪浸润的概念证明，支持mRNA LNP技术作为可扩展和局部替代重组蛋白治疗对抗肌肉变性。进一步优化剂量、给药频率和生物分布对临床转化至关重要。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cellular and molecular bioengineering 生物-生物物理

CiteScore

5.60

自引率

3.60%

发文量

审稿时长

>12 weeks

期刊介绍： The field of cellular and molecular bioengineering seeks to understand, so that we may ultimately control, the mechanical, chemical, and electrical processes of the cell. A key challenge in improving human health is to understand how cellular behavior arises from molecular-level interactions. CMBE, an official journal of the Biomedical Engineering Society, publishes original research and review papers in the following seven general areas: Molecular: DNA-protein/RNA-protein interactions, protein folding and function, protein-protein and receptor-ligand interactions, lipids, polysaccharides, molecular motors, and the biophysics of macromolecules that function as therapeutics or engineered matrices, for example. Cellular: Studies of how cells sense physicochemical events surrounding and within cells, and how cells transduce these events into biological responses. Specific cell processes of interest include cell growth, differentiation, migration, signal transduction, protein secretion and transport, gene expression and regulation, and cell-matrix interactions. Mechanobiology: The mechanical properties of cells and biomolecules, cellular/molecular force generation and adhesion, the response of cells to their mechanical microenvironment, and mechanotransduction in response to various physical forces such as fluid shear stress. Nanomedicine: The engineering of nanoparticles for advanced drug delivery and molecular imaging applications, with particular focus on the interaction of such particles with living cells. Also, the application of nanostructured materials to control the behavior of cells and biomolecules.