Syndecan-4基因敲除小鼠具有更小的肌纤维、增强的Akt/mTOR/S6K1和Notch/HES-1信号通路，以及细胞外基质成分的改变。
Syndecan-4 Mice Have Smaller Muscle Fibers, Increased Akt/mTOR/S6K1 and Notch/HES-1 Pathways, and Alterations in Extracellular Matrix Components.
作者信息
Rønning Sissel Beate, Carlson Cathrine Rein, Aronsen Jan Magnus, Pisconti Addolorata, Høst Vibeke, Lunde Marianne, Liland Kristian Hovde, Sjaastad Ivar, Kolset Svein Olav, Christensen Geir, Pedersen Mona Elisabeth
机构信息
Nofima AS, Ås, Norway.
Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway.
出版信息
Front Cell Dev Biol. 2020 Jul 31;8:730. doi: 10.3389/fcell.2020.00730. eCollection 2020.
BACKGROUND
Extracellular matrix (ECM) remodeling is essential for skeletal muscle development and adaption in response to environmental cues such as exercise and injury. The cell surface proteoglycan syndecan-4 has been reported to be essential for muscle differentiation, but few molecular mechanisms are known. Syndecan-4 mice are unable to regenerate damaged muscle, and display deficient satellite cell activation, proliferation, and differentiation. A reduced myofiber basal lamina has also been reported in syndecan-4 muscle, indicating possible defects in ECM production. To get a better understanding of the underlying molecular mechanisms, we have here investigated the effects of syndecan-4 genetic ablation on molecules involved in ECM remodeling and muscle growth, both under steady state conditions and in response to exercise.
METHODS
Tibialis anterior (TA) muscles from sedentary and exercised syndecan-4 and WT mice were analyzed by immunohistochemistry, real-time PCR and western blotting.
RESULTS
Compared to WT, we found that syndecan-4 mice had reduced body weight, reduced muscle weight, muscle fibers with a smaller cross-sectional area, and reduced expression of myogenic regulatory transcription factors. Sedentary syndecan-4 had also increased mRNA levels of syndecan-2, decorin, collagens, fibromodulin, biglycan, and LOX. Some of these latter ECM components were reduced at protein level, suggesting them to be more susceptible to degradation or less efficiently translated when syndecan-4 is absent. At the protein level, TRPC7 was reduced, whereas activation of the Akt/mTOR/S6K1 and Notch/HES-1 pathways were increased. Finally, although exercise induced upregulation of several of these components in WT, a further upregulation of these molecules was not observed in exercised syndecan-4 mice.
CONCLUSION
Altogether our data suggest an important role of syndecan-4 in muscle development.
背景
细胞外基质（ECM）重塑对于骨骼肌发育以及响应运动和损伤等环境线索时的适应性变化至关重要。据报道，细胞表面蛋白聚糖syndecan-4对肌肉分化必不可少，但目前已知的分子机制较少。Syndecan-4基因敲除小鼠无法再生受损肌肉，并且卫星细胞激活、增殖和分化存在缺陷。此外，在syndecan-4基因敲除小鼠的肌肉中，肌纤维基底膜减少，这表明在ECM产生过程中可能存在缺陷。为了更好地理解潜在的分子机制，我们在此研究了syndecan-4基因敲除对稳态条件下以及运动响应中参与ECM重塑和肌肉生长的分子的影响。
方法
通过免疫组织化学、实时PCR和蛋白质印迹法分析久坐不动和运动后的syndecan-4基因敲除小鼠和野生型（WT）小鼠的胫前肌（TA）。
结果
与野生型相比，我们发现syndecan-4基因敲除小鼠体重减轻、肌肉重量减轻、肌纤维横截面积减小，并且生肌调节转录因子的表达降低。久坐不动的syndecan-4基因敲除小鼠中，syndecan-2、核心蛋白聚糖、胶原蛋白、纤调蛋白、双糖链蛋白聚糖和赖氨氧化酶（LOX）的mRNA水平也有所升高。其中一些ECM成分在蛋白质水平上减少，这表明当syndecan-4缺失时，它们更容易被降解或翻译效率更低。在蛋白质水平上，瞬时受体电位阳离子通道7（TRPC7）减少，而Akt/哺乳动物雷帕霉素靶蛋白（mTOR）/核糖体蛋白S6激酶1（S6K1）和Notch/HES-1信号通路的激活增加。最后，尽管运动可诱导野生型小鼠中这些成分中的几种上调，但在运动后的syndecan-4基因敲除小鼠中未观察到这些分子的进一步上调。
结论
总之，我们的数据表明syndecan-4在肌肉发育中起重要作用。
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