The August Krogh Section for Human Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark.
The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Scand J Med Sci Sports. 2024 Oct;34(10):e14736. doi: 10.1111/sms.14736.
Skeletal muscle mass plays a pivotal role in metabolic function, but conditions such as bed rest or injury often render resistance training impractical. The beta-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 beta-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 beta-adrenergic stimulation or resistance training as well as cell model validation. We report that beta-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 beta-adrenergic-mediated muscle hypertrophy. Treating C2C12 cells with beta-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 beta-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 beta-adrenergic stimulation mimics multiple features of resistance training, and thus the beta-adrenergic receptor may be a target with therapeutic potential in the treatment of muscle wasting conditions without imposing mechanical load.
骨骼肌质量在代谢功能中起着关键作用，但卧床休息或受伤等情况常常使阻力训练变得不切实际。β-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，我们研究了与β-肾上腺素能介导的肌肉肥大相关的蛋白质组变化，将阻力训练作为肥大的比较器。我们利用基于 MS 的蛋白质组学来绘制骨骼肌蛋白质组对β-肾上腺素能刺激或阻力训练的重塑图谱，以及细胞模型验证。我们报告说，β-肾上腺素能刺激在蛋白质组全面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上调和同时的线粒体蛋白下调。大约 20%的蛋白质在两种情况下都受到调节，包括参与类固醇代谢的蛋白质（AKR1C1、AKR1C2、AKRC1C3）、蛋白质折叠（SERPINB1）和细胞外基质组织（COL1A1、COL1A2）。在总体上上调最显著的蛋白质中，有kelch-like 家族成员（KLHL）40 和 41。在后续实验中，我们确定 KLHL41 对β-肾上腺素能介导的肌肉肥大具有新的意义。用β-激动剂处理 C2C12 细胞 96 小时可使肌管直径增加 48%（p<0.001）。这种合成代谢作用被 KLHL41 的预先敲低所消除。使用 siRNA，KLHL41 的丰度降低了 60%，β-激动剂的合成代谢反应减弱（增加了 15%，即在存在 KLHL41 的情况下更大，敲低×处理：p=0.004）。总之，β-肾上腺素能刺激诱导的蛋白质组全面重塑模拟了阻力训练的多个特征，因此β-肾上腺素能受体可能是治疗肌肉消耗疾病的潜在靶点，而无需施加机械负荷。
