Dysferlin regulates cell membrane repair by facilitating injury-triggered acid sphingomyelinase secretion
Dysferlin regulates cell membrane repair by facilitating injury-triggered acid sphingomyelinase secretion
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DOI：
10.1038/cddis.2014.272
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发表时间：
2014-06-01
影响因子：
9
通讯作者：
Jaiswal, J. K.
中科院分区：
文献类型：
--
作者：
Defour, A.;Van der Meulen, J. H.;Jaiswal, J. K.
Dysferlin缺乏会损害受损肌肉的修复，但潜在的细胞机制仍然难以捉摸。为了研究这种现象，我们已经开发了小鼠和人类成肌细胞模型dysferlin病。这些dysferlinopathic成肌细胞进行正常分化，但有缺陷的能力，以修复其细胞膜的局灶性损伤。成像细胞进行修复表明，dysferlin缺陷减少了溶酶体存在于细胞膜上的数量，导致损伤触发的溶酶体胞吐的延迟和减少。我们发现损伤细胞的修复并不涉及通过溶酶体-溶酶体融合形成细胞内膜补丁;相反，单个溶酶体与损伤细胞膜融合，释放酸性鞘磷脂酶（ASM）。ASM分泌减少损伤dysferlinopathic细胞，急性治疗与鞘磷脂酶恢复dysferlinopathic成肌细胞和肌纤维的修复能力。我们的研究结果提供了dysferlin介导的骨骼肌肌膜修复的机制，并确定ASM作为dysferlin病的潜在治疗方法。
Dysferlin deficiency compromises the repair of injured muscle, but the underlying cellular mechanism remains elusive. To study this phenomenon, we have developed mouse and human myoblast models for dysferlinopathy. These dysferlinopathic myoblasts undergo normal differentiation but have a deficit in their ability to repair focal injury to their cell membrane. Imaging cells undergoing repair showed that dysferlin-deficit decreased the number of lysosomes present at the cell membrane, resulting in a delay and reduction in injury-triggered lysosomal exocytosis. We find repair of injured cells does not involve formation of intracellular membrane patch through lysosome-lysosome fusion; instead, individual lysosomes fuse with the injured cell membrane, releasing acid sphingomyelinase (ASM). ASM secretion was reduced in injured dysferlinopathic cells, and acute treatment with sphingomyelinase restored the repair ability of dysferlinopathic myoblasts and myofibers. Our results provide the mechanism for dysferlin-mediated repair of skeletal muscle sarcolemma and identify ASM as a potential therapy for dysferlinopathy.