Role of aberrant activated fibro/adipogenic progenitors and suppressed ferroptosis in disused skeletal muscle atrophy and fatty infiltration.

IF 4.8 3区 医学 Q1 GENETICS & HEREDITY
Jiale Tan, Yuqi Li, Jie Zhang, Beijie Qi, Jiwu Chen, Yaying Sun
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引用次数: 0

Abstract

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.

异常活化的纤维/脂肪祖细胞和抑制的铁下垂在废用骨骼肌萎缩和脂肪浸润中的作用。
肌肉脂肪浸润(MFI)的特征是骨骼肌组织内脂肪的病理积累。以往的研究发现,这一病理现象在衰老、急性肌肉损伤等情况下的进展是由关键细胞群纤维/脂肪生成祖细胞(fibro/adipogenic progenitor, FAPs)的激活和成脂分化引发的,但关于废用骨骼肌萎缩引起的脂肪浸润的研究较少,FAPs在这种情况下的调控作用尚未深入探讨,相关分子机制尚不清楚。在这项研究中,我们对废弃的骨骼肌进行了单细胞RNA测序。随后的分析发现,在这种状态下,FAPs异常增殖,激活的FAPs中铁下垂抑制基因高表达。免疫荧光染色证实了FAPs的增殖和成脂分化,证实了FAPs在废骨骼肌脂肪浸润中的作用。为了进一步验证铁下垂抑制与FAPs激活/成脂分化之间的关系,我们利用常用的铁下垂抑制剂铁抑素-1体外治疗骨骼肌成纤维细胞和FAPs,验证了铁下垂抑制对其成脂/成纤维能力的增强。我们的研究明确了FAPs异常激活对废用骨骼肌MFI的影响,并初步认识到铁下沉对FAPs成脂分化的潜在影响。关键信息:•肌肉脂肪浸润(MFI)的特征是骨骼肌内脂肪的病理积累。纤维/脂肪生成祖细胞(FAPs)被认为是MFI的关键调节因子,但它们在废弃骨骼肌中的相关性尚未明确。•在本研究中,我们对废弃的骨骼肌进行了单细胞RNA测序,发现FAPs的异常增殖以及在这种状态下铁下垂抑制基因的上调。•随后,我们使用铁抑素-1(铁下垂抑制剂)体外治疗骨骼肌成纤维细胞,并验证了铁下垂抑制对其脂肪生成/成纤维能力的增强。•我们的研究明确了FAPs异常激活对废用骨骼肌MFI的影响,并初步认识到铁沉对FAPs成脂分化的潜在影响。
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来源期刊
Journal of Molecular Medicine-Jmm
Journal of Molecular Medicine-Jmm 医学-医学:研究与实验
CiteScore
9.30
自引率
0.00%
发文量
100
审稿时长
1.3 months
期刊介绍: The Journal of Molecular Medicine publishes original research articles and review articles that range from basic findings in mechanisms of disease pathogenesis to therapy. The focus includes all human diseases, including but not limited to: Aging, angiogenesis, autoimmune diseases as well as other inflammatory diseases, cancer, cardiovascular diseases, development and differentiation, endocrinology, gastrointestinal diseases and hepatology, genetics and epigenetics, hematology, hypoxia research, immunology, infectious diseases, metabolic disorders, neuroscience of diseases, -omics based disease research, regenerative medicine, and stem cell research. Studies solely based on cell lines will not be considered. Studies that are based on model organisms will be considered as long as they are directly relevant to human disease.
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