Carlsson, MichalaAli, Mona SadekFrank, EmmaMármol, Joan M.Ali, Mona SadekRaun, Steffen H.Battey, EdmundResen Andersen, NicolineIrazoki, AndreaLund, CamillaHenríquez-Olguín, CarlosKubec Højfeldt, MartinaBlomquist, PaulineDuch Bromer, FrederikMocciaro, GabrieleLodberg, AndreasBrix Folsted Andersen, ChristianEijken, MarcoMæchel Fritzen, AndreasRoland Knudsen, JonasRichter, Erik A.Sylow, Lykke2025-12-042025-12-042025-09-27Molecular Metabolism, Vol. 102 (2025) p. 1-112212-8778https://hdl.handle.net/20.500.12254/7387Purpose: Blocking the Activin receptor type IIA and IIB (ActRIIA/IIB) has clinical potential to increase muscle mass and improve glycemic control in obesity, cancer, and aging. However, the impact of blocking ActRIIA/IIB on strength, metabolic regulation, and insulin action remains unclear. Methods: Here, we investigated the effect of short- (10 mg kg− 1 bw, once, 40h) or long-term (10 mg kg− 1 bw, twice weekly, 21 days) antibody treatment targeting ActRIIA/IIB αActRIIA/IIB) in lean and diet-induced obese mice and engineered human muscle tissue. Results: Short-term α ActRIIA/IIB administration in lean mice increased insulin-stimulated glucose uptake in skeletal muscle by 76—105%. Despite this, αActRIIA/IIB-treated mice exhibited 33% elevated blood glucose and glucose intolerance. Long-term αActRIIA/IIB treatment increased muscle mass (+20%) and reduced fat mass (− 8%) in obese mice but failed to enhance insulin-stimulated glucose uptake in muscle or adipose tissue. Instead, it induced glucose intolerance, cardiac hypertrophy with glycogen accumulation, and elevated hepatic triacylglycerol and glucose output in response to pyruvate. Concomitantly, long-term αActRIIA/IIB treatment increased strength (+30%) in mouse soleus muscle and prevented activin A-induced loss of tissue strength in engineered human muscle tissue. Surprisingly, long-term α ActRIIA/IIB treatment lowered volitional running (− 250%). Conclusions: Our findings demonstrate that, in accordance with human studies, ActRIIA/IIB blockade holds promise for increasing muscle mass, strength, and muscle insulin sensitivity. However, contrary to the improved glycemic control in humans, ActRIIA/IIB blockade in mice causes severe glucose intolerance and lowers voluntary physical activity. Our study underscores the complex metabolic and functional consequences of ActRIIA/IIB blockade, and highlight species differences on glycemic control, which warrant further investigation.enAtribución-NoComercial-CompartirIgual 3.0 Chile (CC BY-NC-SA 3.0 CL)Insulin resistanceActivin receptorBimagrumabObesityMuscle massGlycemic regulationArticlehttps://orcid.org/0000-0002-9315-9365https://doi.org/10.1016/j.molmet.2025.102261