Department of Endocrinology, Metabolism, and Hypertension Research, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Kyoto, Japan.
Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Kyoto, Japan.
Acta Physiol (Oxf). 2018 Mar;222(3). doi: 10.1111/apha.12975. Epub 2017 Oct 19.
The functional significance of the myokines, cytokines and peptides produced and released by muscle cells has not been fully elucidated. The purpose of this study was to identify a myokine with increased secretion levels in muscle cells due to saturated fatty acids and to examine the role of the identified myokine in the regulation of myogenesis.
Human primary myotubes and mouse C2C12 myotubes were used to identify the myokine; its secretion was stimulated by palmitate loading. The role of the identified myokine in the regulation of the activation, proliferation, differentiation and self-renewal was examined in mouse satellite cells (skeletal muscle stem cells).
Palmitate loading promoted the secretion of chemokine (C-X-C motif) ligand 1 (CXCL1) in human primary myotubes, and it also increased CXCL1 gene expression level in C2C12 myotubes in a dose- and time-dependent manner. Palmitate loading increased the production of reactive oxygen species along with the activation of nuclear factor-kappa B (NF-κB) signalling. Pharmacological inhibition of NF-κB signalling attenuated the increase in CXCL1 gene expression induced by palmitate and hydrogen peroxide. Palmitate loading significantly increased CXC receptor 2 gene expression in undifferentiated cells. CXCL1 knockdown attenuated proliferation and myotube formation by satellite cells, with reduced self-renewal. CXCL1 knockdown also significantly decreased the Notch intracellular domain protein level.
These results suggest that secretion of the myokine CXCL1 is stimulated by saturated fatty acids and that CXCL1 promotes myogenesis from satellite cells to maintain skeletal muscle homeostasis.
肌肉细胞产生和释放的肌肉因子、细胞因子和肽的功能意义尚未完全阐明。本研究的目的是鉴定一种因饱和脂肪酸而导致肌肉细胞分泌水平增加的肌肉因子，并研究鉴定出的肌肉因子在调节肌发生中的作用。
使用人原代肌管和小鼠 C2C12 肌管来鉴定肌肉因子；用软脂酸负载刺激其分泌。在小鼠卫星细胞（骨骼肌干细胞）中，研究鉴定出的肌肉因子在调节激活、增殖、分化和自我更新中的作用。
软脂酸负载促进人原代肌管中趋化因子（C-X-C 基序）配体 1（CXCL1）的分泌，并以剂量和时间依赖的方式增加 C2C12 肌管中 CXCL1 基因表达水平。软脂酸负载增加了活性氧的产生，同时激活了核因子-κB（NF-κB）信号通路。NF-κB 信号通路的药理学抑制减弱了软脂酸和过氧化氢诱导的 CXCL1 基因表达增加。软脂酸负载显著增加未分化细胞中 CXC 受体 2 基因表达。CXCL1 敲低减弱了卫星细胞的增殖和肌管形成，自我更新减少。CXCL1 敲低还显著降低了 Notch 细胞内结构域蛋白水平。
这些结果表明，饱和脂肪酸刺激肌肉因子 CXCL1 的分泌，CXCL1 促进卫星细胞的肌发生，以维持骨骼肌的内稳态。
