Several common chronic diseases, muscular dystrophies (MDs), and aging lead to progressive fibrous connective tissue (fibrosis) accumulation in skeletal muscle. Cumulative past evidence points to the role of signaling lipids such as lysophosphatidic acid (LPA) and its receptors (LPARs) in different models of fibrosis. However, the potential contribution of these molecules to the fibrotic process in skeletal muscle has not been explored. Here, we show the expression of ATX/LPA/LPARs axis components in skeletal muscle, which suggests their potential relevance for the biology of this tissue. We investigated if the skeletal muscle responds to the stimulus of intramuscular (IM) LPA injections, finding an early induction of the pro-fibrotic factor connective tissue growth factor/Cellular Communication Network factor 2 (CCN2) and extracellular matrix (ECM) proteins. Also, we found that LPA induces an increase in the number of fibro/adipogenic progenitors (FAPs), which are the primary cellular source of myofibroblasts. These effects were for the most part prevented by the inhibitor Ki16425, which inhibits the LPA receptors LPA₁ and LPA₃, as well as in the LPA₁-KO mice. We also evaluated the in vivo activation of extracellular signal-regulated kinases (ERK 1/2), AKT, c-Jun N-terminal kinase (JNK), and Yes-asocciated protein 1 (YAP) in response to LPA. Our results show that LPA induces ERK 1/2 phosphorylation in WT muscle, but not in LPA₁-KO mice. Treatment with the ERK 1/2 inhibitor U0126 prevented the induction of fibronectin in response to LPA, suggesting that this pathway is involved in LPA-induced fibrosis. Altogether, these results demonstrate that ATX/LPA/LPARs constitute a pro-fibrotic axis and suggest a possible role in muscular diseases.

几种常见的慢性疾病、肌营养不良症 (MDs) 和衰老导致骨骼肌中进行性纤维结缔组织 (纤维化) 积聚。过去的累积证据表明信号脂质如溶血磷脂酸 (LPA) 及其受体 (LPAR) 在不同的纤维化模型中的作用。然而，尚未探索这些分子对骨骼肌纤维化过程的潜在贡献。在这里，我们展示了 ATX/LPA/LPARs 轴成分在骨骼肌中的表达，这表明它们与该组织的生物学具有潜在的相关性。我们调查了骨骼肌是否对肌肉内 (IM) LPA 注射的刺激有反应，发现促纤维化因子结缔组织生长因子/细胞通讯网络因子 2 (CCN2) 和细胞外基质 (ECM) 蛋白的早期诱导。此外，我们发现 LPA 诱导成纤维/脂肪祖细胞 (FAP) 数量的增加，这是肌成纤维细胞的主要细胞来源。这些作用在很大程度上被抑制剂 Ki16425 所阻止，它抑制 LPA 受体 LPA₁和 LPA ₃，以及在 LPA ₁ -KO 小鼠中。我们还评估了细胞外信号调节激酶 (ERK 1/2)、AKT、c-Jun N-末端激酶 (JNK) 和 Yes 相关蛋白 1 (YAP) 响应 LPA的体内激活。我们的结果表明，LPA 在 WT 肌肉中诱导 ERK 1/2 磷酸化，但在 LPA ₁ -KO 小鼠中没有。用 ERK 1/2 抑制剂 U0126 治疗阻止了纤连蛋白对 LPA 的反应，表明该途径参与 LPA 诱导的纤维化。总而言之，这些结果表明 ATX/LPA/LPARs 构成了一个促纤维化轴，并表明可能在肌肉疾病中发挥作用。