Collagen VI deficiency reduces muscle pathology, but does not improve muscle function, in the γ-sarcoglycan-null mouse
Collagen VI deficiency reduces muscle pathology, but does not improve muscle function, in the γ-sarcoglycan-null mouse
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DOI：
10.1093/hmg/ddw018
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发表时间：
2016-04-01
影响因子：
3.5
通讯作者：
Campbell, Kevin P.
中科院分区：
文献类型：
--
作者：
de Greef, Jessica C.;Hamlyn, Rebecca;Campbell, Kevin P.
肌肉营养不良的特征是进行性骨骼肌无力，营养不良的肌肉表现出肌细胞变性和再生、炎症和纤维化。骨骼肌纤维化是细胞外基质组分的过度沉积，包括胶原VI的积累。我们假设，在呈现纤维化的肌营养不良模型中胶原VI的减少将导致肌肉病理减少和肌肉功能改善。为了验证这一假设，我们将γ-肌聚糖缺失小鼠（2C型肢带型肌营养不良症模型）与Col 6a 2缺陷小鼠模型杂交。我们发现，与γ-肌聚糖缺失小鼠相比，所得的γ-肌聚糖缺失/Col 6a 2 Delta ex 5小鼠确实表现出减少的肌肉病理。具体而言，较少的肌纤维退化，纤维大小变化较小，伊文思蓝染料摄取减少，血清肌酸激酶水平较低。令人惊讶的是，尽管肌肉病变减少，肌肉功能没有显著改善。事实上，γ-肌聚糖缺失/Col 6a 2 Delta ex 5小鼠的握力和最大等长强直力甚至低于γ-肌聚糖缺失小鼠。总之，我们的研究结果表明，胶原VI介导的纤维化有助于γ-肌聚糖缺失小鼠的骨骼肌病理学。然而，重要的是，我们的数据还表明，骨骼肌病理学的减少并不一定会导致骨骼肌功能的改善，这应该在未来的转化研究中考虑。
Muscular dystrophy is characterized by progressive skeletal muscle weakness and dystrophic muscle exhibits degeneration and regeneration of muscle cells, inflammation and fibrosis. Skeletal muscle fibrosis is an excessive deposition of components of the extracellular matrix including an accumulation of Collagen VI. We hypothesized that a reduction of Collagen VI in a muscular dystrophy model that presents with fibrosis would result in reduced muscle pathology and improved muscle function. To test this hypothesis, we crossed gamma-sarcoglycan-null mice, a model of limb-girdle muscular dystrophy type 2C, with a Col6a2-deficient mouse model. We found that the resulting gamma-sarcoglycan-null/Col6a2 Delta ex5 mice indeed exhibit reduced muscle pathology compared with gamma-sarcoglycan-null mice. Specifically, fewer muscle fibers are degenerating, fiber size varies less, Evans blue dye uptake is reduced and serum creatine kinase levels are lower. Surprisingly, in spite of this reduction in muscle pathology, muscle function is not significantly improved. In fact, grip strength and maximum isometric tetanic force are even lower in gamma-sarcoglycan-null/Col6a2 Delta ex5 mice than in gamma-sarcoglycan-null mice. In conclusion, our results reveal that Collagen VI-mediated fibrosis contributes to skeletal muscle pathology in gamma-sarcoglycan-null mice. Importantly, however, our data also demonstrate that a reduction in skeletal muscle pathology does not necessarily lead to an improvement of skeletal muscle function, and this should be considered in future translational studies.