Expression of Myomaker and Myomerger in myofibers causes muscle pathology.
Expression of Myomaker and Myomerger in myofibers causes muscle pathology.
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DOI：
10.1186/s13395-023-00317-z
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发表时间：
2023-05-01
期刊：
影响因子：
4.9
通讯作者：
中科院分区：
文献类型：
--
作者：
骨骼肌的发育和再生依赖于肌源性祖细胞的细胞融合来产生多核肌纤维。这些祖细胞利用两种肌肉特异性的融合原，Myomaker和mymerger，它们通过重塑细胞膜来相互融合或与现有的肌纤维融合。Myomaker和Myomerger的表达仅限于分化祖细胞，因为它们在成人肌纤维中未被检测到。然而，Myomaker在肌营养不良小鼠的肌纤维中仍有表达。来自营养不良肌纤维的Myomaker消融导致膜损伤减少，导致与成肌细胞相比，肌纤维中持续的fusogen表达是有害的。建立了dox诱导转基因小鼠，在骨骼肌肌纤维室中异位表达Myomaker或Myomerger。我们量化了肌纤维膜损伤的指标，如血清肌酸激酶和IgM+肌纤维，并评估了一般肌肉组织学，包括中心成核、肌纤维大小和纤维化。肌纤维中Myomaker或mymerger的表达在急性时间点单独引起膜损伤。这种损伤导致肌肉病理，表现为中央有核肌纤维和肌肉萎缩。Myomaker和Myomerger在肌纤维中的双重表达与单独表达任何一种fusogen相比，加重了肌肉病理的几个方面。这些数据表明，虽然肌纤维可以耐受一定程度的Myomaker和mymerger，但超过阈值的单一fusogen表达或两种fusogen的共同表达对肌纤维是有害的。这些结果解释了它们在肌纤维中的表达可能在肌肉病理中产生有害后果的范式，并强调了在肌肉发生和融合过程中高度限制它们的表达的必要性。在线版本包含补充材料，可在10.1186/s13395-023-00317-z获得。
Skeletal muscle development and regeneration depend on cellular fusion of myogenic progenitors to generate multinucleated myofibers. These progenitors utilize two muscle-specific fusogens, Myomaker and Myomerger, which function by remodeling cell membranes to fuse to each other or to existing myofibers. Myomaker and Myomerger expression is restricted to differentiating progenitor cells as they are not detected in adult myofibers. However, Myomaker remains expressed in myofibers from mice with muscular dystrophy. Ablation of Myomaker from dystrophic myofibers results in reduced membrane damage, leading to a model where persistent fusogen expression in myofibers, in contrast to myoblasts, is harmful. Dox-inducible transgenic mice were developed to ectopically express Myomaker or Myomerger in the myofiber compartment of skeletal muscle. We quantified indices of myofiber membrane damage, such as serum creatine kinase and IgM+ myofibers, and assessed general muscle histology, including central nucleation, myofiber size, and fibrosis. Myomaker or Myomerger expression in myofibers independently caused membrane damage at acute time points. This damage led to muscle pathology, manifesting with centrally nucleated myofibers and muscle atrophy. Dual expression of both Myomaker and Myomerger in myofibers exacerbated several aspects of muscle pathology compared to expression of either fusogen by itself. These data reveal that while myofibers can tolerate some level of Myomaker and Myomerger, expression of a single fusogen above a threshold or co-expression of both fusogens is damaging to myofibers. These results explain the paradigm that their expression in myofibers can have deleterious consequences in muscle pathologies and highlight the need for their highly restricted expression during myogenesis and fusion. The online version contains supplementary material available at 10.1186/s13395-023-00317-z.
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DOI：
10.1083/jcb.122.4.809
发表时间：
1993-08
期刊：
The Journal of cell biology
影响因子：
--
作者：
Ervasti JM;Campbell KP
通讯作者：
Campbell KP
影响因子：
12.7
作者：
Granata, AL;Vecchi, C;Corsi, A
通讯作者：
Corsi, A
影响因子：
1.2
作者：
Boldrin, Luisa;Zammit, Peter S.;Morgan, Jennifer E.
通讯作者：
Morgan, Jennifer E.
影响因子：
5.8
作者：
Dumont, Nicolas A.;Bentzinger, C. Florian;Rudnicki, Michael A.
通讯作者：
Rudnicki, Michael A.
影响因子：
3.5
作者：
Harris, Andrew R.;Charras, G. T.
通讯作者：
Charras, G. T.