O'Brien Joseph G, Willis Alexander B, Long Ashlee M, Kwon Jason, Lee GaHyun, Li Frank, Page Patrick G T, Vo Andy H, Hadhazy Michele, Crosbie Rachelle H, Demonbreun Alexis R, McNally Elizabeth M
Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Department of Integrative Biology and Physiology, UCLA, Los Angeles, CA; Department of Neurology David Geffen School of Medicine, UCLA, Los Angeles, CA.
bioRxiv. 2023 Jun 30:2023.06.29.547098. doi: 10.1101/2023.06.29.547098.
Genetic background shifts the severity of muscular dystrophy. In mice, the DBA/2J strain confers a more severe muscular dystrophy phenotype, whereas the Murphy's Roth Large (MRL) strain has "super-healing" properties that reduce fibrosis. A comparative analysis of the null model of Limb Girdle Muscular Dystrophy in the DBA/2J versus MRL strain showed the MRL background was associated with greater myofiber regeneration and reduced structural degradation of muscle. Transcriptomic profiling of dystrophic muscle in the DBA/2J and MRL strains indicated strain-dependent expression of the extracellular matrix (ECM) and TGF-β signaling genes. To investigate the MRL ECM, cellular components were removed from dystrophic muscle sections to generate decellularized "myoscaffolds". Decellularized myoscaffolds from dystrophic mice in the protective MRL strain had significantly less deposition of collagen and matrix-bound TGF-β1 and TGF-β3 throughout the matrix, and dystrophic myoscaffolds from the MRL background were enriched in myokines. C2C12 myoblasts were seeded onto decellularized matrices from MRL and DBA/2J matrices. Acellular myoscaffolds from the dystrophic MRL background induced myoblast differentiation and growth compared to dystrophic myoscaffolds from the DBA/2J matrices. These studies establish that the MRL background also generates its effect through a highly regenerative ECM, which is active even in muscular dystrophy.
遗传背景会改变肌肉萎缩症的严重程度。在小鼠中，DBA/2J品系会导致更严重的肌肉萎缩症表型，而墨菲罗斯大（MRL）品系具有“超强愈合”特性，可减少纤维化。对DBA/2J与MRL品系中肢带型肌肉萎缩症的无效模型进行的比较分析表明，MRL背景与更大程度的肌纤维再生以及肌肉结构降解减少有关。DBA/2J和MRL品系中营养不良肌肉的转录组分析表明，细胞外基质（ECM）和TGF-β信号基因的表达具有品系依赖性。为了研究MRL ECM，从营养不良的肌肉切片中去除细胞成分以生成脱细胞的“肌支架”。来自具有保护作用的MRL品系的营养不良小鼠的脱细胞肌支架在整个基质中胶原蛋白和基质结合的TGF-β1和TGF-β3的沉积明显更少，并且来自MRL背景的营养不良肌支架富含肌动蛋白。将C2C12成肌细胞接种到来自MRL和DBA/2J基质的脱细胞基质上。与来自DBA/2J基质的营养不良肌支架相比，来自营养不良MRL背景的无细胞肌支架诱导成肌细胞分化和生长。这些研究表明，MRL背景也通过高度再生的ECM产生其作用，即使在肌肉萎缩症中该ECM也是活跃的。
