Clenbuterol, but not Inhaled Formoterol, Upregulates the Sarcomere Stabilizer KLHL41 to a Similar Extent as Resistance Training in Human Skeletal Muscle

Beta₂-adrenergic agonists are widely used for bronchial relief in respiratory conditions such as asthma and exercise-induced bronchoconstriction. However, this drug class has also been shown to have muscle anabolic properties. Kelch-Like Family Member 41 (KLHL41) is a sarcomeric protein implicated in muscle remodeling and hypertrophy. In this study, we examined the effects of oral clenbuterol, therapeutic inhaled formoterol, and resistance training on KLHL41 protein abundance in human skeletal muscle. KLHL41 levels were measured by immunoblotting in vastus lateralis muscle biopsies from healthy adults following 2 weeks of oral clenbuterol administration, 6 weeks of inhaled formoterol at therapeutic doses, or 8 weeks of resistance training. We also assessed sex differences and the effects of acute versus prolonged interventions. Prolonged oral clenbuterol administration significantly increased KLHL41 abundance compared to placebo (p < 0.001), with a magnitude similar to that observed after resistance training (p < 0.01), whereas therapeutic inhaled formoterol had no effect on KLHL41 levels. Neither acute clenbuterol administration nor a single resistance training session altered KLHL41 abundance, and no sex differences were observed in baseline KLHL41 levels. These findings indicate that beta₂-adrenergic stimulation via oral clenbuterol, but not therapeutic inhalation of formoterol, promotes sarcomeric remodeling through KLHL41-related pathways similar to those activated by resistance training. The distinct effects of these agents on KLHL41 support current anti-doping regulations prohibiting clenbuterol use and highlight KLHL41 as a potential molecular marker of skeletal muscle adaptation to hypertrophic stimuli.