Kinesin light chain 1 stabilizes insulin receptor substrate 1 to regulate the IGF-1-AKT signaling pathway during myoblast differentiation
Kinesin light chain 1 stabilizes insulin receptor substrate 1 to regulate the IGF-1-AKT signaling pathway during myoblast differentiation
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DOI：
10.1096/fj.202201065rr
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发表时间：
2024-02-15
期刊：
影响因子：
4.8
通讯作者：
Wu，Haobo
中科院分区：
文献类型：
--
作者：
Qu，Zihao;Shi，Linjing;Wu，Haobo
IGF信号通路在调节骨骼肌发生中起着关键作用。我们已经证明，KIF5B是Kinesin-1马达的重链，通过调节IGF-p38MAPK的激活来促进成肌细胞的分化。然而，运动蛋白轻链(KLC)在IGF途径和成肌细胞分化中的作用仍不清楚。在这项研究中，我们发现Klc1在肌肉再生过程中上调，而在衰老小鼠肌肉和MDX(X连锁肌肉营养不良)小鼠营养不良肌肉中下调。功能获得和功能丧失实验进一步表明，KLc1促进AKT-mTOR活性，并正向调节肌源性分化。我们进一步发现，IGF-1信号的关键节点IRS1的表达水平在Klc1缺失的成肌细胞中下调。免疫共沉淀研究表明，IRS1通过其PTB结构域与KLc1的88-154个氨基酸序列相互作用。值得注意的是，来自小鼠和人类的衰老和骨质疏松症骨骼肌样本中都发现了Klc1水平的降低。综上所述，我们的发现提示Klc1通过稳定IRS1在肌肉发生过程中对IGF-AKT通路的调节起着至关重要的作用，这可能最终影响肌肉相关疾病的发展。
The IGF signaling pathway plays critical role in regulating skeletal myogenesis. We have demonstrated that KIF5B, the heavy chain of kinesin‐1 motor, promotes myoblast differentiation through regulating IGF‐p38MAPK activation. However, the roles of the kinesin light chain (Klc) in IGF pathway and myoblast differentiation remain elusive. In this study, we found that Klc1 was upregulated during muscle regeneration and downregulated in senescence mouse muscles and dystrophic muscles from mdx (X‐linked muscular dystrophic) mice. Gain‐ and loss‐of‐function experiments further displayed that Klc1 promotes AKT–mTOR activity and positively regulates myogenic differentiation. We further identified that the expression levels of IRS1, the critical node of IGF‐1 signaling, are downregulated in Klc1‐depleted myoblasts. Coimmunoprecipitation study revealed that IRS1 interacted with the 88‐154 amino acid sequence of Klc1 via its PTB domain. Notably, the reduced Klc1 levels were found in senescence and osteoporosis skeletal muscle samples from both mice and human. Taken together, our findings suggested a crucial role of Klc1 in the regulation of IGF‐AKT pathway during myogenesis through stabilizing IRS1, which might ultimately influence the development of muscle‐related disorders.