Clenbuterol induces lean mass and muscle protein accretion, but attenuates cardiorespiratory fitness and desensitizes muscle β2-adrenergic signalling

Abstract

The β₂-adrenergic agonist clenbuterol is widely abused because of its purported fat-burning actions, muscle accretion properties and performance enhancing effects, and yet it remains unexplored in randomized controlled trials. In the present study, we subjected 11 healthy men (aged 18-40 years) to two 2 week cycles of oral clenbuterol (80 µg day^-1) or placebo, separated by a 3 week washout. During each cycle, we assessed body composition, cardiorespiratory fitness, sprint power output, cardiac left ventricular mass and intravascular blood volume. We obtained vastus lateralis muscle biopsies and analysed them for protein content, 3-hydroxyacyl CoA dehydrogenase (HAD) activity, oxidative phosphorylation complex (OXPHOS) abundance, platelet endothelial cell adhesion molecule (PECAM-1) abundance and β₂-adrenergic signalling. Compared to placebo, clenbuterol induced a 0.91 kg lean mass gain (95% confidence interval = 0.02-1.81, P < 0.05) but had no effect on fat mass. Clenbuterol reduced maximal oxygen uptake by 7% (P < 0.001) and exercise capacity by 4% (P < 0.001) but had no effects on sprint power output, left ventricular mass, intravascular blood volume or haemoglobin mass. Clenbuterol increased muscle protein content (P < 0.05) and PECAM-1 abundance (P < 0.05) but repressed HAD activity (P < 0.01) and OXPHOS complex V abundance (P < 0.05). Clenbuterol markedly activated muscle protein kinase A (P < 0.001) and phosphorylated ribosomal protein S6 (Ser235/236) but this effect declined during the 2 week cycle. Although a 2 week clenbuterol cycle effectively induces lean mass gain and muscle protein accretion, it negatively affects cardiorespiratory fitness, represses muscle oxidative capacity, and induces tolerance in β₂-adrenergic signalling and ribosomal protein S6 phosphorylation. The adverse effects of clenbuterol along with its muscle anabolic actions justify its prohibition in elite sports. KEY POINTS: Clenbuterol, a potent β₂-adrenergic agonist, has purported fat-burning and muscle accretion properties. However, its purported effects, along with its potential adverse effects on cardiorespiratory fitness, remain unexplored in humans. A short 2 week clenbuterol cycle induces lean mass gain and muscle protein accretion in healthy young men. Clenbuterol induces β₂-adrenergic signalling and phosphorylates RpS6^Ser235/236 in skeletal muscle, but this signalling response is attenuated with repeated exposure. Clenbuterol negatively affects cardiorespiratory fitness and represses muscle oxidative capacity. Clenbuterol does not affect left ventricular mass, intravascular blood volume or haemoglobin mass.

Trial registration: ClinicalTrials.gov NCT03860870.

Keywords: doping; muscle hypertrophy; repartitioning; β‐adrenergic receptor; β‐agonist.