Beta₂-Adrenergic Stimulation Induces Resistance Training-Like Adaptations in Human Skeletal Muscle: Potential Role of KLHL41

Skeletal muscle mass plays a pivotal role in metabolic function, but conditions such as bed rest or injury often render resistancetraining impractical. The beta 2 -adrenergic receptor has been highlighted as a potential target to promote muscle hypertrophyand treat atrophic conditions. Here, we investigate the proteomic changes associated with beta 2 -adrenergic-mediated muscle hy-pertrophy, using resistance training as a hypertrophic comparator. We utilize MS-based proteomics to map skeletal muscle pro-teome remodeling in response to beta 2 -adrenergic stimulation or resistance training as well as cell model validation. We reportthat beta 2 -adrenergic stimulation mimics multiple features of resistance training in proteome-wide remodeling, comprising sys-tematic upregulation of ribosomal subunits and concomitant downregulation of mitochondrial proteins. Approximately 20% ofproteins 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 up-regulated proteins were kelch-like family members (KLHL) 40 and 41. In follow-up experiments, we identify KLHL41 as havingnovel implications for beta 2 -adrenergic-mediated muscle hypertrophy. Treating C2C12 cells with beta 2 -agonist for 96 h increasedmyotube diameter by 48% (p < 0.001). This anabolic effect was abolished by prior knockdown of KLHL41. Using siRNA, KLHL41abundance was decreased by 60%, and the anabolic response to beta 2 -agonist was diminished (+ 15%, i.e., greater in the presenceof KLHL41, knock-down × treatment: p = 0.004). In conclusion, protein-wide remodeling induced by beta 2 -adrenergic stimula-tion mimics multiple features of resistance training, and thus the beta 2 -adrenergic receptor may be a target with therapeuticpotential in the treatment of muscle wasting conditions without imposing mechanical load.