Department of Cell Biology and Molecular Medicine, New Jersey Medical School, Rutgers University, Newark, New Jersey.
Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, Missouri.
Am J Physiol Cell Physiol. 2019 Oct 1;317(4):C813-C824. doi: 10.1152/ajpcell.00146.2019. Epub 2019 Jul 31.
Reduction in the expression of sarcolipin (SLN), an inhibitor of sarco(endo)plasmic reticulum (SR) Ca-ATPase (SERCA), ameliorates severe muscular dystrophy in mice. However, the mechanism by which SLN inhibition improves muscle structure remains unclear. Here, we describe the previously unknown function of SLN in muscle differentiation in Duchenne muscular dystrophy (DMD). Overexpression of SLN in CC resulted in decreased SERCA pump activity, reduced SR Ca load, and increased intracellular Ca () concentration. In addition, SLN overexpression resulted in altered expression of myogenic markers and poor myogenic differentiation. In dystrophin-deficient dog myoblasts and myotubes, SLN expression was significantly high and associated with defective cycling. The dystrophic dog myotubes were less branched and associated with decreased autophagy and increased expression of mitochondrial fusion and fission proteins. Reduction in SLN expression restored these changes and enhanced dystrophic dog myoblast fusion during differentiation. In summary, our data suggest that SLN upregulation is an intrinsic secondary change in dystrophin-deficient myoblasts and could account for the mishandling, which subsequently contributes to poor myogenic differentiation. Accordingly, reducing SLN expression can improve the cycling and differentiation of dystrophic myoblasts. These findings provide cellular-level supports for targeting SLN expression as a therapeutic strategy for DMD.
肌浆球蛋白（SLN）是肌质（内质）网 Ca-ATP 酶（SERCA）的抑制剂，其表达减少可改善小鼠的严重肌肉营养不良。然而，SLN 抑制改善肌肉结构的机制仍不清楚。在这里，我们描述了 SLN 在杜氏肌营养不良症（DMD）肌肉分化中的先前未知功能。在 CC 中过表达 SLN 会导致 SERCA 泵活性降低、SR Ca 负荷减少和细胞内 Ca（i）浓度增加。此外，SLN 过表达导致成肌标志物的表达改变和成肌分化不良。在缺乏 dystrophin 的犬成肌细胞和肌管中，SLN 表达明显升高，并与 循环缺陷相关。营养不良的犬肌管分支较少，与自噬减少和线粒体融合和分裂蛋白表达增加有关。降低 SLN 表达可恢复这些变化，并在分化过程中增强营养不良的犬成肌细胞融合。总之，我们的数据表明，SLN 的上调是营养不良的成肌细胞中的内在继发变化，可能是 处理不当的原因，进而导致成肌分化不良。因此，降低 SLN 表达可以改善营养不良的成肌细胞的 循环和分化。这些发现为靶向 SLN 表达作为 DMD 的治疗策略提供了细胞水平的支持。
