Tan Jiale, Li Yuqi, Zhang Jie, Qi Beijie, Chen Jiwu, Sun Yaying
Department of Sports Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Hongkou District, No. 85 Wujin Road, Shanghai, 200080, China.
School of Medicine, Tongji University, Shanghai, 200090, China.
J Mol Med (Berl). 2025 May 3. doi: 10.1007/s00109-025-02548-7.
Muscle fatty infiltration (MFI) was characterized by the pathological accumulation of fat within skeletal muscle tissue. Previous studies have found that the progress of this pathological phenomenon in aging, acute muscle injury, and other conditions was triggered by the activation and adipogenic differentiation of the key cell population, fibro/adipogenic progenitors (FAPs), but there were few studies on the fat infiltration caused by disused skeletal muscle atrophy, and the regulatory role of FAPs in this situation has not been deeply explored, leaving the related molecular mechanisms still unknown. In this study, we conducted single-cell RNA sequencing on the disused skeletal muscle. The aberrant proliferation of FAPs in this state was found by subsequent analysis, along with the high expression of the ferroptosis inhibitory gene in the activated FAPs. By immunofluorescence staining, we verified the proliferation and adipogenic differentiation of FAPs, which proved the role of FAPs in fat infiltration of disused skeletal muscle. In order to further verify the relationship between ferroptosis inhibition and FAPs activation/adipogenic differentiation, we used ferrostatin-1, a commonly used ferroptosis inhibitor, to treat skeletal muscle fibroblasts and FAPs in vitro, and verified the enhancement of ferroptosis inhibition on their adipogenic/fibrogenic ability. Our study pinpointed the effect of aberrant activation of FAPs on MFI in disused skeletal muscle, and preliminarily recognized the potential effect of ferroptosis on the adipogenic differentiation of FAPs. KEY MESSAGES: • Muscle fatty infiltration (MFI) was characterized by the pathological accumulation of fat within skeletal muscle. Fibro/adipogenic progenitors (FAPs) were thought to be crucial regulators of MFI, but their correlations in disused skeletal muscle were unspecified. • In this study, we conducted single-cell RNA sequencing on the disused skeletal muscle and recognized the aberrant proliferation of FAPs along with the upregulated ferroptosis inhibition genes in this status. • Subsequently, we used ferrostatin-1 (ferroptosis inhibitor) to treat skeletal muscle fibroblasts in vitro, and verified the enhancement of ferroptosis inhibition on their adipogenic/fibrogenic ability. • Our study pinpointed the effect of aberrant activation of FAPs on MFI in disused skeletal muscle, and preliminarily recognized the potential effect of ferroptosis on the adipogenic differentiation of FAPs.
肌肉脂肪浸润（MFI）的特征是骨骼肌组织内脂肪的病理性蓄积。先前的研究发现，在衰老、急性肌肉损伤及其他情况下，这种病理现象的进展是由关键细胞群——成纤维/脂肪生成祖细胞（FAPs）的激活和脂肪生成分化所引发的，但关于废用性骨骼肌萎缩导致的脂肪浸润的研究较少，且FAPs在这种情况下的调节作用尚未得到深入探究，相关分子机制仍不清楚。在本研究中，我们对废用性骨骼肌进行了单细胞RNA测序。通过后续分析发现了这种状态下FAPs的异常增殖，以及激活的FAPs中铁死亡抑制基因的高表达。通过免疫荧光染色，我们验证了FAPs的增殖和脂肪生成分化，这证明了FAPs在废用性骨骼肌脂肪浸润中的作用。为了进一步验证铁死亡抑制与FAPs激活/脂肪生成分化之间的关系，我们使用常用的铁死亡抑制剂铁抑素-1在体外处理骨骼肌成纤维细胞和FAPs，并验证了铁死亡抑制对其脂肪生成/纤维化能力的增强作用。我们的研究明确了FAPs异常激活对废用性骨骼肌MFI的影响，并初步认识到铁死亡对FAPs脂肪生成分化的潜在作用。关键信息：• 肌肉脂肪浸润（MFI）的特征是骨骼肌内脂肪的病理性蓄积。成纤维/脂肪生成祖细胞（FAPs）被认为是MFI的关键调节因子，但其在废用性骨骼肌中的相关性尚不明确。• 在本研究中，我们对废用性骨骼肌进行了单细胞RNA测序，并认识到在这种状态下FAPs的异常增殖以及铁死亡抑制基因的上调。• 随后，我们使用铁抑素-1（铁死亡抑制剂）在体外处理骨骼肌成纤维细胞，并验证了铁死亡抑制对其脂肪生成/纤维化能力的增强作用。• 我们的研究明确了FAPs异常激活对废用性骨骼肌MFI的影响，并初步认识到铁死亡对FAPs脂肪生成分化的潜在作用。
