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 Kubec Højfeldt, Pauline Blomquist, Frederik Duch Bromer, Gabriele Mocciaro, Andreas Lodber, Christian Brix Folsted Andersen, Marco Eijken, Andreas Mæchel Fritzen, Jonas Roland Knudsen, Erik A Richter, Lykke Sylow
{"title":"激活素受体类型IIA/IIB阻断增加肌肉质量和力量，但损害小鼠的血糖控制。","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 Kubec Højfeldt, Pauline Blomquist, Frederik Duch Bromer, Gabriele Mocciaro, Andreas Lodber, Christian Brix Folsted Andersen, Marco Eijken, Andreas Mæchel Fritzen, Jonas Roland Knudsen, Erik A Richter, Lykke Sylow","doi":"10.1016/j.molmet.2025.102261","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>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.</p><p><strong>Methods: </strong>Here, we investigated the effect of short- (10 mg kg<sup>-1</sup> bw, once, 40h) or long-term (10 mg kg<sup>-1</sup> bw, twice weekly, 21 days) antibody treatment targeting ActRIIA/IIB (αActRIIA/IIB) in lean and diet-induced obese mice and engineered human muscle tissue.</p><p><strong>Results: </strong>Short-term α ActRIIA/IIB administration in lean mice increased insulin-stimulated glucose uptake in skeletal muscle by 76-105%. Despite this, α ActRIIA/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 α ActRIIA/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%).</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":" ","pages":"102261"},"PeriodicalIF":6.6000,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Activin receptor type IIA/IIB 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 Kubec Højfeldt, Pauline Blomquist, Frederik Duch Bromer, Gabriele Mocciaro, Andreas Lodber, Christian Brix Folsted Andersen, Marco Eijken, Andreas Mæchel Fritzen, Jonas Roland Knudsen, Erik A Richter, Lykke Sylow\",\"doi\":\"10.1016/j.molmet.2025.102261\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Purpose: </strong>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.</p><p><strong>Methods: </strong>Here, we investigated the effect of short- (10 mg kg<sup>-1</sup> bw, once, 40h) or long-term (10 mg kg<sup>-1</sup> bw, twice weekly, 21 days) antibody treatment targeting ActRIIA/IIB (αActRIIA/IIB) in lean and diet-induced obese mice and engineered human muscle tissue.</p><p><strong>Results: </strong>Short-term α ActRIIA/IIB administration in lean mice increased insulin-stimulated glucose uptake in skeletal muscle by 76-105%. Despite this, α ActRIIA/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 α ActRIIA/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%).</p><p><strong>Conclusions: </strong>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.</p>\",\"PeriodicalId\":18765,\"journal\":{\"name\":\"Molecular Metabolism\",\"volume\":\" \",\"pages\":\"102261\"},\"PeriodicalIF\":6.6000,\"publicationDate\":\"2025-09-27\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Molecular Metabolism\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.molmet.2025.102261\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ENDOCRINOLOGY & METABOLISM\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Metabolism","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.molmet.2025.102261","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
Activin receptor type IIA/IIB blockade increases muscle mass and strength, but compromises glycemic control in mice.
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-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, α ActRIIA/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 α ActRIIA/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.
期刊介绍：
Molecular Metabolism is a leading journal dedicated to sharing groundbreaking discoveries in the field of energy homeostasis and the underlying factors of metabolic disorders. These disorders include obesity, diabetes, cardiovascular disease, and cancer. Our journal focuses on publishing research driven by hypotheses and conducted to the highest standards, aiming to provide a mechanistic understanding of energy homeostasis-related behavior, physiology, and dysfunction.
We promote interdisciplinary science, covering a broad range of approaches from molecules to humans throughout the lifespan. Our goal is to contribute to transformative research in metabolism, which has the potential to revolutionize the field. By enabling progress in the prognosis, prevention, and ultimately the cure of metabolic disorders and their long-term complications, our journal seeks to better the future of health and well-being.
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