Department of Biomedical and Clinical Sciences "Luigi Sacco" (DIBIC), Università degli Studi di Milano, 20157 Milano, Italy.
Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, 47921 Rimini, Italy.
Cells. 2021 Nov 5;10(11):3028. doi: 10.3390/cells10113028.
Skeletal muscle regeneration is a complex process involving crosstalk between immune cells and myogenic precursor cells, i.e., satellite cells. In this scenario, macrophage recruitment in damaged muscles is a mandatory step for tissue repair since pro-inflammatory M1 macrophages promote the activation of satellite cells, stimulating their proliferation and then, after switching into anti-inflammatory M2 macrophages, they prompt satellite cells' differentiation into myotubes and resolve inflammation. Here, we show that acid sphingomyelinase (ASMase), a key enzyme in sphingolipid metabolism, is activated after skeletal muscle injury induced in vivo by the injection of cardiotoxin. ASMase ablation shortens the early phases of skeletal muscle regeneration without affecting satellite cell behavior. Of interest, ASMase regulates the balance between M1 and M2 macrophages in the injured muscles so that the absence of the enzyme reduces inflammation. The analysis of macrophage populations indicates that these events depend on the altered polarization of M1 macrophages towards an M2 phenotype. Our results unravel a novel role of ASMase in regulating immune response during muscle regeneration/repair and suggest ASMase as a supplemental therapeutic target in conditions of redundant inflammation that impairs muscle recovery.
骨骼肌再生是一个复杂的过程，涉及免疫细胞和肌源性前体细胞（即卫星细胞）之间的串扰。在这种情况下，受损肌肉中巨噬细胞的募集是组织修复的必要步骤，因为促炎 M1 巨噬细胞促进卫星细胞的激活，刺激其增殖，然后在转换为抗炎 M2 巨噬细胞后，促使卫星细胞分化为肌管并解决炎症。在这里，我们表明，酸性鞘磷脂酶（ASMase）是鞘脂代谢中的关键酶，在体内通过注射心脏毒素诱导骨骼肌损伤后被激活。ASMase 缺失缩短了骨骼肌再生的早期阶段，而不影响卫星细胞的行为。有趣的是，ASMase 调节损伤肌肉中 M1 和 M2 巨噬细胞之间的平衡，从而减少炎症。对巨噬细胞群体的分析表明，这些事件取决于 M1 巨噬细胞向 M2 表型的极化改变。我们的研究结果揭示了 ASMase 在调节肌肉再生/修复过程中的免疫反应中的新作用，并表明 ASMase 是一种补充治疗靶点，可用于过度炎症会损害肌肉恢复的情况。
