Department of Biomedical Sciences, University of Padova, Padova, Italy.
Interuniversity Institute of Myology, Italy.
Exp Physiol. 2020 Nov;105(11):1895-1906. doi: 10.1113/EP088603. Epub 2020 Sep 25.
What is the central question of the study? What are the consequences of reducing circulating sphingosine-1-phosphate (S1P) for muscle physiology in the murine model of Duchenne muscular dystrophy (DMD)? What is the main result and its importance? Reduction of the circulating S1P level in mdx mice aggravates the dystrophic phenotype, as seen by an increase in fibre atrophy, fibrosis and loss of specific force, suggesting that S1P signalling is a potential therapeutic target in DMD. Although further studies are needed, plasma S1P levels have the intriguing possibility of being used as a biomarker for disease severity, an important issue in DMD.
Sphingosine-1-phosphate (S1P) is an important regulator of skeletal muscle properties. The dystrophin-deficient mdx mouse possesses low levels of S1P (∼50%) compared with wild type. Increased S1P availability was demonstrated to ameliorate the dystrophic phenotype in Drosophila and in mdx mice. Here, we analysed the effects produced by further reduction of S1P availability on the mass, force and regenerative capacity of dystrophic mdx soleus. Circulating S1P was neutralized by a specific anti-S1P antibody (S1P-Ab) known to lower the extracellular concentration of this signalling lipid. The S1P-Ab was administered intraperitoneally in adult mdx mice every 2 days for the duration of experiments. Soleus muscle properties were analysed 7 or 14 days after the first injection. The decreased availability of circulating S1P after the 14 day treatment reduced mdx soleus fibre cross-sectional area (-16%, P < 0.05), an effect that was associated with an increase in markers of proteolytic (MuRF1 and atrogin-1) and autophagic (p62 and LC3-II/LC3-I ratio) pathways. Moreover, an increase of fibrosis was also observed (+26%, P < 0.05). Notably, the treatment also caused a reduction of specific tetanic tension (-29%, P < 0.05). The mdx soleus regenerative capacity was only slightly influenced by reduced S1P. In conclusion, neutralization of circulating S1P reduces the mass and specific force and increases fibrosis of mdx soleus muscle, thus worsening the dystrophic phenotype. The results confirm that active, functional S1P signalling might counteract the progression of soleus mdx pathology and validate the pathway as a potential therapeutic target for muscular dystrophies.
研究的核心问题是什么？减少杜氏肌营养不良症（DMD）小鼠模型中循环鞘氨醇-1-磷酸（S1P）对肌肉生理学有什么影响？主要结果及其重要性是什么？减少 mdx 小鼠的循环 S1P 水平会加重纤维萎缩、纤维化和特定力丧失等营养不良表型，表明 S1P 信号是 DMD 的潜在治疗靶点。尽管还需要进一步研究，但血浆 S1P 水平有可能成为疾病严重程度的生物标志物，这是 DMD 中的一个重要问题。
鞘氨醇-1-磷酸（S1P）是调节骨骼肌特性的重要物质。与野生型相比，肌营养不良蛋白缺陷型 mdx 小鼠的 S1P 水平较低（约 50%）。增加 S1P 的可用性被证明可以改善果蝇和 mdx 小鼠的营养不良表型。在这里，我们分析了进一步降低 S1P 可用性对营养不良 mdx 比目鱼肌质量、力量和再生能力的影响。通过一种已知能降低这种信号脂质细胞外浓度的特异性抗 S1P 抗体（S1P-Ab）来中和循环 S1P。S1P-Ab 每隔两天通过腹腔注射给药，持续实验时间。第一次注射后 7 或 14 天分析比目鱼肌的特性。经过 14 天的治疗后，循环 S1P 减少会降低 mdx 比目鱼肌纤维横截面积（减少 16%，P<0.05），这与蛋白水解（MuRF1 和 atrogin-1）和自噬（p62 和 LC3-II/LC3-I 比值）途径标志物的增加有关。此外，还观察到纤维化增加（增加 26%，P<0.05）。值得注意的是，该治疗还导致特定的强直张力降低（减少 29%，P<0.05）。减少 S1P 对 mdx 比目鱼肌的再生能力影响不大。总之，中和循环 S1P 会降低 mdx 比目鱼肌的质量和特定力，并增加纤维化，从而使营养不良表型恶化。结果证实，活性、功能性 S1P 信号可能会阻止比目鱼肌 mdx 病理的进展，并验证该途径作为肌肉营养不良的潜在治疗靶点。
