肌纤维特异性 FoxP1 在胰腺癌诱发的肌肉萎缩中的作用

IF 5 2区 生物学 Q2 CELL BIOLOGY
Martin M Schonk, Jeremy B Ducharme, Daria Neyroud, Rachel L Nosacka, Haley O Tucker, Sarah M Judge, Andrew R Judge
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引用次数: 0

摘要

癌症恶病质影响着多达 80% 的癌症患者,并导致生活质量和生存率下降。我们以前曾证实,转录抑制因子叉头盒 P1(FoxP1)在恶病质小鼠和癌症患者的骨骼肌中上调,在骨骼肌中过表达时足以诱发恶病质的病理特征。然而,肌纤维衍生的 FoxP1 在正常肌肉生理学和癌症诱导的肌肉萎缩中的作用在很大程度上仍未得到探索。为了填补这一空白,我们产生了一个FoxP1肌纤维特异性消减的条件性小鼠品系(FoxP1SkmKO),并发现在无癌症的小鼠中,骨骼肌纤维中FoxP1的缺失会导致雄性和雌性小鼠的肌纤维体积增大,雄性小鼠的肌肉质量显著增加。针对小鼠 KPC 胰腺肿瘤负荷,我们发现肌纤维衍生的 FoxP1 是癌症诱导的雄性小鼠肌肉萎缩和膈肌无力所必需的。总之,我们的研究结果确定了肌纤维特异性 FoxP1 是骨骼肌的负调控因子,在癌症背景下具有性别特异性差异。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Role of myofiber-specific FoxP1 in pancreatic cancer-induced muscle wasting.

Cancer cachexia affects up to 80% of patients with cancer and results in reduced quality of life and survival. We previously demonstrated that the transcriptional repressor Forkhead box P1 (FoxP1) is upregulated in the skeletal muscle of cachectic mice and people with cancer, and when overexpressed in skeletal muscle, it is sufficient to induce pathological features characteristic of cachexia. However, the role of myofiber-derived FoxP1 in both normal muscle physiology and cancer-induced muscle wasting remains largely unexplored. To address this gap, we generated a conditional mouse line with myofiber-specific ablation of FoxP1 (FoxP1SkmKO) and found that in cancer-free mice, deletion of FoxP1 in skeletal myofibers resulted in increased myofiber size in both males and females, with a significant increase in muscle mass in males. In response to murine KPC pancreatic tumor burden, we found that myofiber-derived FoxP1 mediates cancer-induced muscle wasting and diaphragm muscle weakness in male but not female mice. In summary, our findings identify myofiber-specific FoxP1 as a negative regulator of skeletal muscle with sex-specific differences in the context of cancer.NEW & NOTEWORTHY Here we identify myofiber-derived FoxP1 as a negative regulator of skeletal muscle with sex-specific effects in cancer. Under cancer-free conditions, FoxP1 knockout increased myofiber size in male and female mice. However, in response to pancreatic cancer, FoxP1 myofiber-specific deletion attenuated muscle wasting and weakness in males but not females. This highlights the need to consider sexual dimorphism in cancer-induced muscle pathologies and provides evidence suggesting that targeting FoxP1 could help mitigate these effects in males.

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来源期刊
CiteScore
9.10
自引率
1.80%
发文量
252
审稿时长
1 months
期刊介绍: The American Journal of Physiology-Cell Physiology is dedicated to innovative approaches to the study of cell and molecular physiology. Contributions that use cellular and molecular approaches to shed light on mechanisms of physiological control at higher levels of organization also appear regularly. Manuscripts dealing with the structure and function of cell membranes, contractile systems, cellular organelles, and membrane channels, transporters, and pumps are encouraged. Studies dealing with integrated regulation of cellular function, including mechanisms of signal transduction, development, gene expression, cell-to-cell interactions, and the cell physiology of pathophysiological states, are also eagerly sought. Interdisciplinary studies that apply the approaches of biochemistry, biophysics, molecular biology, morphology, and immunology to the determination of new principles in cell physiology are especially welcome.
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