Skeletal muscle mass plays a pivotal role in metabolic function, but conditions such as bed rest or injury often render resistance training impractical. The beta2‐adrenergic receptor has been highlighted as a potential target to promote muscle hypertrophy and treat atrophic conditions. Here, we investigate the proteomic changes associated with beta2‐adrenergic‐mediated muscle hypertrophy, using resistance training as a hypertrophic comparator. We utilize MS‐based proteomics to map skeletal muscle proteome remodeling in response to beta2‐adrenergic stimulation or resistance training as well as cell model validation. We report that beta2‐adrenergic stimulation mimics multiple features of resistance training in proteome‐wide remodeling, comprising systematic upregulation of ribosomal subunits and concomitant downregulation of mitochondrial proteins. Approximately 20% of proteins were regulated in both conditions, comprising proteins involved in steroid metabolism (AKR1C1, AKR1C2, AKRC1C3), protein‐folding (SERPINB1), and extracellular matrix organization (COL1A1, COL1A2). Among overall most significantly upregulated proteins were kelch‐like family members (KLHL) 40 and 41. In follow‐up experiments, we identify KLHL41 as having novel implications for beta2‐adrenergic‐mediated muscle hypertrophy. Treating C2C12 cells with beta2‐agonist for 96 h increased myotube diameter by 48% (p < 0.001). This anabolic effect was abolished by prior knockdown of KLHL41. Using siRNA, KLHL41 abundance was decreased by 60%, and the anabolic response to beta2‐agonist was diminished (+ 15%, i.e., greater in the presence of KLHL41, knock‐down × treatment: p = 0.004). In conclusion, protein‐wide remodeling induced by beta2‐adrenergic stimulation mimics multiple features of resistance training, and thus the beta2‐adrenergic receptor may be a target with therapeutic potential in the treatment of muscle wasting conditions without imposing mechanical load.

中文翻译：

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β2-肾上腺素能刺激诱导人体骨骼肌阻力训练样适应：KLHL41 的潜在作用


骨骼肌质量在新陈代谢功能中起着关键作用，但卧床休息或受伤等情况往往使阻力训练变得不切实际。β2-肾上腺素能受体已被强调为促进肌肉肥大和治疗萎缩性疾病的潜在靶点。在这里，我们使用阻力训练作为肥大比较对象，研究了与 β2-肾上腺素能介导的肌肉肥大相关的蛋白质组学变化。我们利用基于 MS 的蛋白质组学来绘制骨骼肌蛋白质组重塑，以响应 β2-肾上腺素能刺激或阻力训练以及细胞模型验证。我们报道 β2-肾上腺素能刺激在蛋白质组范围的重塑中模拟了阻力训练的多个特征，包括核糖体亚基的系统性上调和伴随的线粒体蛋白下调。在这两种情况下，大约 20% 的蛋白质都受到调节，包括参与类固醇代谢 （AKR1C1、AKR1C2、AKRC1C3）、蛋白质折叠 （SERPINB1） 和细胞外基质组织 （COL1A1、COL1A2） 的蛋白质。总体上调最显着的蛋白质是 kelch 样家族成员 （KLHL） 40 和 41。在后续实验中，我们确定 KLHL41 对 β2-肾上腺素能介导的肌肉肥大具有新的意义。用 β2 激动剂处理 C2C12 细胞 96 小时，肌管直径增加了 48% （p < 0.001）。这种合成代谢作用被先前的 KLHL41 敲低所消除。使用 siRNA，KLHL41 丰度降低 60%，对 β2 激动剂的合成代谢反应降低 （+ 15%，即在 KLHL41 存在下更大，敲低×处理：p = 0.004）。 总之，β2-肾上腺素能刺激诱导的全蛋白重塑模拟了阻力训练的多种特征，因此 β2-肾上腺素能受体可能是治疗肌肉萎缩状况的具有治疗潜力的靶点，而不会施加机械负荷。