BackgroundMuscle atrophy can cause muscle dysfunction and weakness. Krüppel‐like factor 13 (KLF13), a central regulator of cellular energy metabolism, is highly expressed in skeletal muscles and implicated in the pathogenesis of several diseases. This study investigated the role of KLF13 in muscle atrophy, which could be a novel therapeutic target.MethodsThe effects of gene knockdown and pharmacological targeting of KLF13 on skeletal muscle atrophy were investigated using cell‐based and animal models. Clofoctol, an antibiotic and KLF13 agonist, was also investigated as a candidate for repurposing. The mechanisms related to skeletal muscle atrophy were assessed by measuring the expression levels and activation statuses of key regulatory pathways and validated using gene knockdown and RNA sequencing.ResultsIn a dexamethasone‐induced muscle atrophy mouse model, the KLF13 knockout group had decreased muscle strength (N) (1.77 ± 0.10 vs. 1.48 ± 0.16, P < 0.01), muscle weight (%) [gastrocnemius (Gas): 76.0 ± 5.69 vs. 60.7 ± 7.23, P < 0.001; tibialis anterior (TA): 75.8 ± 6.21 vs. 67.5 ± 5.01, P < 0.05], and exhaustive running distance (m) (495.5 ± 64.8 vs. 315.5 ± 60.9, P < 0.05) compared with the control group. KLF13 overexpression preserved muscle mass (Gas: 100 ± 6.38 vs. 120 ± 14.4, P < 0.01) and the exhaustive running distance (423.8 ± 59.04 vs. 530.2 ± 77.45, P < 0.05) in an in vivo diabetes‐induced skeletal muscle atrophy model. Clofoctol treatment protected against dexamethasone‐induced muscle atrophy. Myotubes treated with dexamethasone, an atrophy‐inducing glucocorticoid, were aggravated by KLF13 knockout, but anti‐atrophic effects were achieved by inducing KLF13 overexpression. We performed a transcriptome analysis and luciferase reporter assays to further explore this mechanism, finding that delta‐like 4 (Dll4) was a novel target gene of KLF13. The KLF13 transcript repressed Dll4, inhibiting the Dll4‐Notch2 axis and preventing muscle atrophy. Dexamethasone inhibited KLF13 expression by inhibiting myogenic differentiation 1 (i.e., MYOD1)‐mediated KLF13 transcriptional activation and promoting F‐Box and WD repeat domain containing 7 (i.e., FBXW7)‐mediated KLF13 ubiquitination.ConclusionsThis study sheds new light on the mechanisms underlying skeletal muscle atrophy and potential drug targets. KLF13 regulates muscle atrophy and is a potential therapeutic target. Clofoctol is an attractive compound for repurposing studies to treat skeletal muscle atrophy.

中文翻译：

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KLF13抑制Dll4肌肉Notch2轴改善肌肉萎缩


背景肌肉萎缩可导致肌肉功能障碍和无力。 Krüppel 样因子 13 (KLF13) 是细胞能量代谢的中心调节因子，在骨骼肌中高表达，并与多种疾病的发病机制有关。本研究探讨了 KLF13 在肌肉萎缩中的作用，这可能是一个新的治疗靶点。方法KLF13使用基于细胞和动物模型研究了骨骼肌萎缩的影响。 Clofoctol（一种抗生素和 KLF13 激动剂）也作为重新利用的候选药物进行了研究。通过测量关键调控途径的表达水平和激活状态来评估与骨骼肌萎缩相关的机制，并使用基因敲除和 RNA 测序进行验证。结果在地塞米松诱导的肌肉萎缩小鼠模型中， KLF13敲除组肌肉力量（N）下降（1.77±0.10 vs. 1.48±0.16，磷< 0.01)，肌肉重量 (%) [腓肠肌 (Gas)：76.0 ± 5.69 对比 60.7 ± 7.23，磷< 0.001；胫骨前肌 (TA)：75.8 ± 6.21 与 67.5 ± 5.01，磷< 0.05]，以及详尽的跑步距离（米）（495.5 ± 64.8 vs. 315.5 ± 60.9，磷< 0.05）与对照组相比。 KLF13过度表达保留了肌肉质量（气体：100 ± 6.38 与 120 ± 14.4，磷< 0.01）和详尽的运行距离（423.8 ± 59.04 vs. 530.2 ± 77.45，磷< 0.05）在体内糖尿病引起的骨骼肌萎缩模型中。氯福克酚治疗可预防地塞米松引起的肌肉萎缩。 用地塞米松（一种诱导萎缩的糖皮质激素）治疗的肌管因以下原因而加重： KLF13敲除，但抗萎缩作用是通过诱导实现的KLF13过度表达。我们进行了转录组分析和荧光素酶报告基因检测，以进一步探索这一机制，发现 delta-like 4 ( DLL4 ）是KLF13的一个新靶基因。 KLF13 转录物抑制 Dll4，抑制 Dll4-Notch2 轴并防止肌肉萎缩。地塞米松抑制KLF13通过抑制肌源性分化 1（即 MYOD1）介导的 KLF13 转录激活并促进含有 7（即 FBXW7）介导的 F-Box 和 WD 重复结构域介导的 KLF13 泛素化来表达。结论这项研究为骨骼肌萎缩和骨骼肌萎缩的机制提供了新的线索。潜在的药物靶点。 KLF13 调节肌肉萎缩，是一个潜在的治疗靶点。 Clofoctol 是一种有吸引力的化合物，可用于治疗骨骼肌萎缩的重新利用研究。