Expression profile and overexpression outcome indicate a role for βKlotho in skeletal muscle fibro/adipogenesis
Expression profile and overexpression outcome indicate a role for βKlotho in skeletal muscle fibro/adipogenesis
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DOI：
10.1111/febs.13682
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发表时间：
2016-05-01
期刊：
影响因子：
5.4
通讯作者：
Yablonka-Reuveni, Zipora
中科院分区：
文献类型：
--
作者：
Phelps, Michael;Stuelsatz, Pascal;Yablonka-Reuveni, Zipora
骨骼肌的再生在整个生命过程中都是必需的，以确保最佳性能。因此，更好地了解参与肌肉修复的常驻细胞是至关重要的。肌肉修复依赖于卫星细胞（SC），常驻肌源性祖细胞，但也涉及间质细胞，包括脂肪细胞/脂肪细胞祖细胞（FAP）的贡献。为了阐明成纤维细胞生长因子（FGF）信号在这两个细胞群中的作用，我们先前分析了新鲜分离的细胞的FGF受体（FGFR）签名。四个Fgfr基因的转录分析揭示了不同的表达谱的SC和FAP，提高了这两种细胞类型有不同的FGF介导的过程的可能性。在这里，我们追求这一假设，探索Klotho基因的作用，其产物已知作为内分泌FGF亚家族的FGFR共受体。在培养物中分析分离的SC和FAP群体，其分别表现出自发的成肌或成脂分化。在两个群体中均未检测到α Klotho表达。β Klotho表达，虽然在SC中未检测到，但在进入成脂分化的FAP中强烈上调，与一组成脂基因的表达一致，并且在细胞内脂滴的出现之前。在小鼠细胞系模型中β Klotho的过表达增强了NIH 3 T3成纤维细胞中的脂肪形成，但对C2 C12肌源性细胞没有影响。我们的研究支持β Klotho在骨骼肌脂肪形成/脂肪形成中的促脂肪形成作用，并呼吁进一步研究FGF-FGFR-β Klotho轴参与与衰老和肌营养不良症中骨骼肌功能恶化相关的脂肪形成/脂肪形成浸润。
Regeneration of skeletal muscles is required throughout life to ensure optimal performance. Therefore, a better understanding of the resident cells involved in muscle repair is essential. Muscle repair relies on satellite cells (SCs), the resident myogenic progenitors, but also involves the contribution of interstitial cells including fibro/adipocyte progenitors (FAPs). To elucidate the role of the fibroblast growth factor (FGF) signaling in these two cell populations, we previously analyzed freshly isolated cells for their FGF receptor (FGFR) signature. Transcript analysis of the four Fgfr genes revealed distinct expression profiles for SCs and FAPs, raising the possibility that these two cell types have different FGF-mediated processes. Here, we pursued this hypothesis exploring the role of the Klotho genes, whose products are known to function as FGFR co-receptors for the endocrine FGF subfamily. Isolated SC and FAP populations were analyzed in culture, exhibiting spontaneous myogenic or adipogenic differentiation, respectively. alpha Klotho expression was not detected in either population. beta Klotho expression, while not detected in SCs, was strongly upregulated in FAPs entering adipogenic differentiation, coinciding with expression of a panel of adipogenic genes and preceding the appearance of intracellular lipid droplets. Overexpression of beta Klotho in mouse cell line models enhanced adipogenesis in NIH3T3 fibroblasts but had no effect on C2C12 myogenic cells. Our study supports a pro-adipogenic role for beta Klotho in skeletal muscle fibro/adipogenesis and calls for further research on involvement of the FGF-FGFR-beta Klotho axis in the fibro/adipogenic infiltration associated with functional deterioration of skeletal muscle in aging and muscular dystrophy.