Dong Yanjun, Silva Kleiton Augusto Santos, Dong Yanlan, Zhang Liping
Nephrology Division, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA; Beijing An Zhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing, China; and.
Nephrology Division, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA; Nephrology Division, Department of Medicine, Federal University of São Paulo, São Paulo, Brazil.
FASEB J. 2014 Sep;28(9):4123-32. doi: 10.1096/fj.14-254011. Epub 2014 Jun 19.
An increase in intramuscular adipocyte tissue (IMAT) is associated with glucose dysregulation, decreased muscle strength, and increased risk of disability. Unfortunately, the mechanisms stimulating intramuscular adipogenesis remain unclear. We found that dexamethasone (Dex) administration to mice with injured muscles stimulates the accumulation of IMAT. To identify precursors of these adipocytes, we isolated satellite cells and fibro/adipogenic progenitors (FAPs) from muscle; satellite cells did not differentiate into adipocytes even following Dex treatment. In contrast, Dex stimulated FAP differentiation into adipocytes. In vivo, we transplanted purified FAPs from transgenic, EGFP mice into the injured muscles of C57/BL6 mice and found that Dex administration stimulated adipogenesis from FAP-EGFP. The increase in adipogenesis depended on Dex-induced inhibition of interleukin-4 (IL-4). In the injured muscle of IL-4-knockout mice, the levels of adipocytes were increased, while in the injured muscles of Dex-treated mice with IL-4 injections, adipogenesis was suppressed. In cultured FAPs, IL-4 inhibited Dex-induced conversion of FAPs into adipocytes; this did not occur in FAPs expressing knockdown of the IL-4 receptor. Thus, we concluded that glucocorticoids stimulate FAPs to differentiate into adipocytes in injured muscles. This process is blocked by IL-4, suggesting that interfering with IL-4 signaling could prevent adipogenesis in muscle.
肌内脂肪细胞组织（IMAT）增加与葡萄糖调节异常、肌肉力量下降以及残疾风险增加有关。遗憾的是，刺激肌内脂肪生成的机制仍不清楚。我们发现，给肌肉受伤的小鼠注射地塞米松（Dex）会刺激IMAT的积累。为了确定这些脂肪细胞的前体，我们从肌肉中分离出卫星细胞和成纤维/脂肪生成祖细胞（FAPs）；即使经过Dex处理，卫星细胞也不会分化为脂肪细胞。相反，Dex刺激FAPs分化为脂肪细胞。在体内，我们将来自转基因EGFP小鼠的纯化FAPs移植到C57/BL6小鼠的受伤肌肉中，发现注射Dex会刺激FAP-EGFP发生脂肪生成。脂肪生成的增加依赖于Dex诱导的白细胞介素-4（IL-4）抑制。在IL-4基因敲除小鼠的受伤肌肉中，脂肪细胞水平升高，而在注射IL-4的Dex处理小鼠的受伤肌肉中，脂肪生成受到抑制。在培养的FAPs中，IL-4抑制Dex诱导的FAPs向脂肪细胞的转化；在表达IL-4受体敲低的FAPs中则不会发生这种情况。因此，我们得出结论，糖皮质激素刺激受伤肌肉中的FAPs分化为脂肪细胞。这一过程被IL-4阻断，表明干扰IL-4信号传导可以防止肌肉中的脂肪生成。
