Beta 2 -Adrenergic Stimulation Induces Resistance Training-Like Adaptations in Human Skeletal Muscle: Potential Role of KLHL41

• Published in: Scandinavian journal of medicine & science in sports Vol. 34; no. 10; p. e14736
• Main Authors: Jessen, Søren, Quesada, Júlia Prats, Di Credico, Andrea, Moreno-Justicia, Roger, Wilson, Richard, Jacobson, Glenn, Bangsbo, Jens, Deshmukh, Atul S, Hostrup, Morten
• Format: Journal Article
• Language: English
• Published: Denmark 01.10.2024
• Subjects: Adaptation, Physiological; Adrenergic beta-2 Receptor Agonists - pharmacology; Adult; Animals; Cell Line; Humans; Male; Mice; Muscle Proteins - metabolism; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Proteome; Proteomics; Receptors, Adrenergic, beta-2 - metabolism; Resistance Training; Young Adult; atrophy; strength training; muscle hypertrophy; kelch‐like; target
• ISSN: 0905-7188; 1600-0838
• 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.