State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Fudan-Yale Center for Biomedical Research, Innovation Center for International Cooperation of Genetics and Development, Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Children's Hospital of Fudan University, Fudan University, Shanghai, China.
State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Fudan-Yale Center for Biomedical Research, Innovation Center for International Cooperation of Genetics and Development, Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Children's Hospital of Fudan University, Fudan University, Shanghai, China; Present address: Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China.
Exp Cell Res. 2020 Nov 15;396(2):112297. doi: 10.1016/j.yexcr.2020.112297. Epub 2020 Sep 25.
Mutations in the Lmod3 gene have been identified as a genetic cause of nemaline myopathy. However, the mechanism underlying this disease and the function of Lmod3 remain largely unknown. In this study, we found that Lmod3 knockdown in C2C12 cells impaired myoblast differentiation, whereas enforced Lmod3 expression enhanced such differentiation. We also discovered that myoblast proliferation was promoted by Lmod3 overexpression but impeded by its knockdown. Additionally, knockdown of Lmod3 led to apoptosis in myoblasts. Concurrently, forced Lmod3 expression in C2C12 cells contributed to activation of the AKT and ERK pathways during myoblast differentiation and proliferation, respectively. Conversely, knockdown of Lmod3 in C2C12 cells produced the opposite results. Furthermore, administration of IGF-1, a booster of both AKT and ERK pathways, partially rescued the inhibitory effect of Lmod3 knockdown on both differentiation and proliferation of C2C12 cells. These results suggest that Lmod3 promotes differentiation and proliferation of myoblasts through the AKT and ERK pathways, respectively.
Lmod3 基因突变已被确定为杆状体肌病的遗传原因。然而，这种疾病的发病机制和 Lmod3 的功能在很大程度上仍然未知。在这项研究中，我们发现 C2C12 细胞中的 Lmod3 敲低会损害成肌细胞分化，而强制表达 Lmod3 则增强了这种分化。我们还发现 Lmod3 的过表达促进了成肌细胞的增殖，而敲低则阻碍了增殖。此外，Lmod3 的敲低导致成肌细胞凋亡。同时，在 C2C12 细胞中强制表达 Lmod3 分别有助于 AKT 和 ERK 通路在成肌细胞分化和增殖过程中的激活。相反，C2C12 细胞中 Lmod3 的敲低产生了相反的结果。此外，IGF-1（AKT 和 ERK 通路的增强剂）的给药部分挽救了 Lmod3 敲低对 C2C12 细胞分化和增殖的抑制作用。这些结果表明，Lmod3 通过 AKT 和 ERK 通路分别促进成肌细胞的分化和增殖。
