Beta<sub>2</sub>‐Adrenergic Stimulation Induces Resistance Training‐Like Adaptations in Human Skeletal Muscle: Potential Role of <scp>KLHL41</scp>
Søren Jessen, Júlia Prats Quesada, Andrea Di Credico, Roger Moreno‐Justicia, Richard Wilson, Glenn A. Jacobson, Jens Bangsbo, Atul S. Deshmukh, Morten Hostrup
Abstract
ABSTRACT 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 2 ‐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 2 ‐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 2 ‐adrenergic stimulation or resistance training as well as cell model validation. We report that beta 2 ‐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 2 ‐adrenergic‐mediated muscle hypertrophy. Treating C2C12 cells with beta 2 ‐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 2 ‐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 2 ‐adrenergic stimulation mimics multiple features of resistance training, and thus the beta 2 ‐adrenergic receptor may be a target with therapeutic potential in the treatment of muscle wasting conditions without imposing mechanical load.