Blockade of activin type II receptors with a dual anti-ActRIIA/IIB antibody is critical to promote maximal skeletal muscle hypertrophy

Morvan, Frédéric; Rondeau, Jean‐Michel; Zou, Chao; Minetti, Giulia; Scheufler, Clemens; Scharenberg, Meike; Jacobi, Carsten; Brebbia, Pascale; Ritter, Veronique; Toussaint, Gauthier; Koelbing, Claudia; Leber, Xavier Charles; Schilb, Alain; Witte, Florian; Lehmann, Sylvie; Koch, Elke; Geisse, Sabine; Glass, David J.; Lach-Trifilieff, Estelle

doi:10.1073/pnas.1707925114

Cited by 96 publications

(85 citation statements)

References 46 publications

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“…We treated TOV21G tumour‐bearing mice with an ActRII neutralizing antibody (CDD866). CDD866 efficiently inhibits the binding of ligands, including activin A and myostatin, to both ActRIIA and ActRIIB …”

Section: Resultsmentioning

confidence: 99%

“…In our mouse model, we find that treating tumour‐bearing mice with an ACVR2 neutralizing antibody not only reverts muscle mass to normal level but also causes a significant increase in muscle mass. Possibly, this relates to the ability of this antibody to block the binding of both activin A and myostatin to the ACVR2 . Myostatin deficiency has previously been shown to be highly anabolic .…”

Section: Discussionmentioning

confidence: 99%

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Autocrine activin A signalling in ovarian cancer cells regulates secretion of interleukin 6, autophagy, and cachexia

Pettersen

Andersen

Veen

et al. 2019

J cachexia sarcopenia muscle

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Background The majority of patients with advanced cancer develop cachexia, a weight loss syndrome that severely reduces quality of life and limits survival. Our understanding of the underlying mechanisms that cause the condition is limited, and there are currently no treatment options that can completely reverse cachexia. Several tumour‐derived factors and inflammatory mediators have been suggested to contribute to weight loss in cachectic patients. However, inconsistencies between studies are recurrent. Activin A and interleukin 6 (IL‐6) are among the best studied factors that seem to be important, and several studies support their individual role in cachexia development. Methods We investigated the interplay between activin A and IL‐6 in the cachexia‐inducing TOV21G cell line, both in culture and in tumours in mice. We previously found that the human TOV21G cells secrete IL‐6 that induces autophagy in reporter cells and cachexia in mice. Using this established cachexia cell model, we targeted autocrine activin A by genetic, chemical, and biological approaches. The secretion of IL‐6 from the cancer cells was determined in both culture and tumour‐bearing mice by a species‐specific ELISA. Autophagy reporter cells were used to monitor the culture medium for autophagy‐inducing activities, and muscle mass changes were evaluated in tumour‐bearing mice. Results We show that activin A acts in an autocrine manner to promote the synthesis and secretion of IL‐6 from cancer cells. By inhibiting activin A signalling, the production of IL‐6 from the cancer cells is reduced by 40–50% (up to 42% reduction on protein level, P = 0.0048, and 48% reduction on mRNA level, P = 0.0308). Significantly reduced IL‐6 secretion (P < 0.05) from the cancer cells is consistently observed when using biological, chemical, and genetic approaches to interfere with the autocrine activin A loop. Inhibiting activin signalling also reduces the ability of the cancer cells to accelerate autophagy in non‐cancerous cells (up to 43% reduced autophagy flux, P = 0.0006). Coherent to the in vitro data, the use of an anti‐activin receptor 2 antibody in cachectic tumour‐bearing mice reduces serum levels of cancer cell‐derived IL‐6 by 62% (from 417 to 159 pg/mL, P = 0.03), and, importantly, it reverses cachexia and counteracts loss of all measured muscle groups (P < 0.0005). Conclusions Our data support a functional link between activin A and IL‐6 signalling pathways and indicate that interference with activin A‐induced IL‐6 secretion from the tumour has therapeutic potential for cancer‐induced cachexia.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Autocrine activin A signalling in ovarian cancer cells regulates secretion of interleukin 6, autophagy, and cachexia

Pettersen

Andersen

Veen

et al. 2019

J cachexia sarcopenia muscle

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“…One possible mechanism for muscle wasting in cachexia is increased signalling through activin receptor ligands, such as myostatin and activins . Myostatin and activins negatively regulate muscle mass through binding to their receptors activin receptor type 2 (ACVR2) A and B . Blocking these ligands or their receptors can increase muscle mass and prevent muscle wasting in various animal models, but also in humans …”

Section: Introductionmentioning

confidence: 99%

“…Myostatin and activins negatively regulate muscle mass through binding to their receptors activin receptor type 2 (ACVR2) A and B . Blocking these ligands or their receptors can increase muscle mass and prevent muscle wasting in various animal models, but also in humans …”

Section: Introductionmentioning

confidence: 99%

“…[8][9][10][11] Myostatin and activins negatively regulate muscle mass through binding to their receptors activin receptor type 2 (ACVR2) A and B. 12,13 Blocking these ligands or their receptors can increase muscle mass and prevent muscle wasting in various animal models, [12][13][14][15][16] but also in humans. 17,18 Prevention of cancer associated cachexia by blocking ACVR2 ligands with either soluble receptor (sACVR2B) 9,16 or neutralizing antibody against the receptors 14 has previously been shown to improve survival without an effect on primary tumour growth in preclinical animal models.…”

Section: Introductionmentioning

confidence: 99%

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Treating cachexia using soluble ACVR2B improves survival, alters mTOR localization, and attenuates liver and spleen responses

Nissinen

Hentilä

Penna

et al. 2018

J cachexia sarcopenia muscle

161

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BackgroundCancer cachexia increases morbidity and mortality, and blocking of activin receptor ligands has improved survival in experimental cancer. However, the underlying mechanisms have not yet been fully uncovered.MethodsThe effects of blocking activin receptor type 2 (ACVR2) ligands on both muscle and non‐muscle tissues were investigated in a preclinical model of cancer cachexia using a recombinant soluble ACVR2B (sACVR2B‐Fc). Treatment with sACVR2B‐Fc was applied either only before the tumour formation or with continued treatment both before and after tumour formation. The potential roles of muscle and non‐muscle tissues in cancer cachexia were investigated in order to understand the possible mechanisms of improved survival mediated by ACVR2 ligand blocking.ResultsBlocking of ACVR2 ligands improved survival in tumour‐bearing mice only when the mice were treated both before and after the tumour formation. This occurred without effects on tumour growth, production of pro‐inflammatory cytokines or the level of physical activity. ACVR2 ligand blocking was associated with increased muscle (limb and diaphragm) mass and attenuation of both hepatic protein synthesis and splenomegaly. Especially, the effects on the liver and the spleen were observed independent of the treatment protocol. The prevention of splenomegaly by sACVR2B‐Fc was not explained by decreased markers of myeloid‐derived suppressor cells. Decreased tibialis anterior, diaphragm, and heart protein synthesis were observed in cachectic mice. This was associated with decreased mechanistic target of rapamycin (mTOR) colocalization with late‐endosomes/lysosomes, which correlated with cachexia and reduced muscle protein synthesis.ConclusionsThe prolonged survival with continued ACVR2 ligand blocking could potentially be attributed in part to the maintenance of limb and respiratory muscle mass, but many observed non‐muscle effects suggest that the effect may be more complex than previously thought. Our novel finding showing decreased mTOR localization in skeletal muscle with lysosomes/late‐endosomes in cancer opens up new research questions and possible treatment options for cachexia.

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Bimagrumab vs Optimized Standard of Care for Treatment of Sarcopenia in Community-Dwelling Older Adults

Rooks¹,

Swan²,

Goswami

et al. 2020

JAMA Netw Open

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IMPORTANCE The potential benefit of novel skeletal muscle anabolic agents to improve physical function in people with sarcopenia and other muscle wasting diseases is unknown. OBJECTIVE To confirm the safety and efficacy of bimagrumab plus the new standard of care on skeletal muscle mass, strength, and physical function compared with standard of care alone in community-dwelling older adults with sarcopenia. DESIGN, SETTING, AND PARTICIPANTS This double-blind, placebo-controlled, randomized clinical trial was conducted at 38 sites in 13 countries among community-dwelling men and women aged 70 years and older meeting gait speed and skeletal muscle criteria for sarcopenia. The study was

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Blockade of activin type II receptors with a dual anti-ActRIIA/IIB antibody is critical to promote maximal skeletal muscle hypertrophy

Cited by 96 publications

References 46 publications

Autocrine activin A signalling in ovarian cancer cells regulates secretion of interleukin 6, autophagy, and cachexia

Autocrine activin A signalling in ovarian cancer cells regulates secretion of interleukin 6, autophagy, and cachexia

Treating cachexia using soluble ACVR2B improves survival, alters mTOR localization, and attenuates liver and spleen responses

Bimagrumab vs Optimized Standard of Care for Treatment of Sarcopenia in Community-Dwelling Older Adults

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