Activin receptor type IIA/B blockade increases muscle mass and strength, but compromises glycemic control in mice

Authors: Michala Carlsson, Emma Frank, Joan M. Màrmol, Mona Sadek Ali, Steffen H. Raun, Edmund Battey, Nicoline Resen Andersen, Andrea Irazoki, Camilla Lund, Carlos Henríquez-Olguin, Martina Hubec Højfeldt, Pauline Blomquist, Frederik Duch Brome, Andreas Lodberg, Christian Brix Folsted Andersen, Marco Eijken, Jonas Roland Knudsen, Erik A. Richter, Lykke Sylow

Originally Published in: bioRxiv (June 2025) (Link to Original Posting)

Short abstract

Purpose

Blocking the Activin receptor type IIA and B (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 once, 40h) or long-term (10 mg/kg twice weekly, 21 days) antibody targeting ActRIIA/IIB (αActRIIA/IIBab) in lean and diet-induced obese mice and engineered human muscle tissue.

Results

Short-term αActRIIA/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 fasting blood glucose and glucose intolerance. Moreover, long-term αActRIIA/IIB treatment increased average muscle mass (20%) and reduced fat mass (-8%) in obese mice but did not change insulin-stimulated glucose uptake in skeletal muscle or adipose tissue, yet induced marked glucose intolerance, and increased hepatic glucose output in response to pyruvate. Concomitantly, long-term αActRIIA/IIBab 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 αActRIIA/IIBab treatment lowered volitional running (-250%).

Conclusion

Our findings demonstrate that, in accordance with human studies, ActRIIA/IIB blockade holds promise for increasing muscle mass, strength, and 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.

Competing Interest Statement

Competing interests: CH-O, PB, MHH, and JRK are employed at Novo Nordisk S/A. Andreas Lodberg has served as a consultant or has received advisory fees from Acarios, Aureka Biotechnologies, Bluejay Therapeutics, Epirium Bio, and Morgan Stanley. Andreas Lodberg has performed sponsored research for Keros Therapeutics. Declaration of generative AI and AI-assisted technologies in the writing process. Statement: During the preparation of this work, the authors used ChatGPT in order to do minor corrections and shortening of sentences. After using this tool/service, the authors reviewed and edited the content as needed and take full responsibility for the content of the published article.

Funder Information Declared

The Danish Council for Independent Research, Medical Sciences, DFF-4004-00233

The Novo Nordisk Foundation, NNF16OC0023418, NNF18OC0032082