Activin A induces skeletal muscle catabolism via p38β mitogen‐activated protein kinase

Ding, Hui; Zhang, Guohua; Sin, Ka Wai Thomas; Liu, Zhelong; Lin, Ren Kuo; Li, Min; Li, Yi Ping

doi:10.1002/jcsm.12145

Cited by 64 publications

(71 citation statements)

References 55 publications

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“…NF‐κB has been shown to collaborate with p38 MAPK to induce IL‐6 expression . Also, p38 MAPK is one of the signalling mediators downstream of activin A . We found that coinciding with reduced pNF‐κB and IL‐6 levels, interference with activin A signalling reduced the level of phospho‐p38 in the cancer cells ( Figure I).…”

Section: Resultsmentioning

confidence: 74%

“…32 Also, p38 MAPK is one of the signalling mediators downstream of activin A. 33 We found that coinciding with reduced pNF-κB and IL-6 levels, interference with activin A signalling reduced the level of phospho-p38 in the cancer cells ( Figure 3I). These data suggest that p38 MAPK and NF-κB play a role in activin A-induced production of IL-6.…”

Section: Activin a Is Important For Secretion Of The Autophagy-accelementioning

confidence: 78%

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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: 74%

Section: Activin a Is Important For Secretion Of The Autophagy-accelementioning

confidence: 78%

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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“…Neither was Smad3 activated by CM relative to growth media at any time points. However, p38 MAPK activation was prominent at 15 and 30 min ( Figure D), consistent with the described signalling of activins on C2C12 myotubes . The activation state persisted through 1 and 5 h and disappeared by 24 h after CM treatment (data not shown).…”

Section: Resultsmentioning

confidence: 99%

“…However, p38 MAPK activation was prominent at 15 and 30 min ( Figure 4D), consistent with the described signalling of activins on C2C12 myotubes. 42 The activation state persisted through 1 and 5 h and disappeared by 24 h after CM treatment (data not shown). Notably, there was a much stronger p38 MAPK activation signal in cells treated with activin high -KPC32908 CM than activin low -KPC32043 CM.…”

Section: Pancreatic Ductal Adenocarcinoma Cells Express Factors That mentioning

confidence: 89%

The systemic activin response to pancreatic cancer: implications for effective cancer cachexia therapy

Zhong

Pons

Poirier

et al. 2019

J cachexia sarcopenia muscle

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BackgroundPancreatic ductal adenocarcinoma (PDAC) is a particularly lethal malignancy partly due to frequent, severe cachexia. Serum activin correlates with cachexia and mortality, while exogenous activin causes cachexia in mice.MethodsIsoform‐specific activin expression and activities were queried in human and murine tumours and PDAC models. Activin inhibition was by administration of soluble activin type IIB receptor (ACVR2B/Fc) and by use of skeletal muscle specific dominant negative ACVR2B expressing transgenic mice. Feed‐forward activin expression and muscle wasting activity were tested in vivo and in vitro on myotubes.ResultsMurine PDAC tumour‐derived cell lines expressed activin‐βA but not activin‐βB. Cachexia severity increased with activin expression. Orthotopic PDAC tumours expressed activins, induced activin expression by distant organs, and produced elevated serum activins. Soluble factors from PDAC elicited activin because conditioned medium from PDAC cells induced activin expression, activation of p38 MAP kinase, and atrophy of myotubes. The activin trap ACVR2B/Fc reduced tumour growth, prevented weight loss and muscle wasting, and prolonged survival in mice with orthotopic tumours made from activin‐low cell lines. ACVR2B/Fc also reduced cachexia in mice with activin‐high tumours. Activin inhibition did not affect activin expression in organs. Hypermuscular mice expressing dominant negative ACVR2B in muscle were protected for weight loss but not mortality when implanted with orthotopic tumours. Human tumours displayed staining for activin, and expression of the gene encoding activin‐βA (INHBA) correlated with mortality in patients with PDAC, while INHBB and other related factors did not.ConclusionsPancreatic adenocarcinoma tumours are a source of activin and elicit a systemic activin response in hosts. Human tumours express activins and related factors, while mortality correlates with tumour activin A expression. PDAC tumours also choreograph a systemic activin response that induces organ‐specific and gene‐specific expression of activin isoforms and muscle wasting. Systemic blockade of activin signalling could preserve muscle and prolong survival, while skeletal muscle‐specific activin blockade was only protective for weight loss. Our findings suggest the potential and need for gene‐specific and organ‐specific interventions. Finally, development of more effective cancer cachexia therapy might require identifying agents that effectively and/or selectively inhibit autocrine vs. paracrine activin signalling.

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“…104 The GH/IGF-1 axis is controlled by several GH secretagogues that have been the subject of experimental therapies. 115 Circulating activin A levels have also been shown to be an independent predictor of survival in cancer patients. 105 Ghrelin, which is primarily produced in the fundus of the stomach, has been used in disease-related anorexia and conditions of muscle loss like sarcopenia and cachexia.…”

Section: Chronic Heart Failure and Muscle Maintenancementioning

confidence: 99%

Skeletal muscle wasting in chronic heart failure

2018

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Patients suffering from chronic heart failure (CHF) show an increased prevalence (~20% in elderly CHF patients) of loss of muscle mass and muscle function (i.e. sarcopenia) compared with healthy elderly people. Sarcopenia, which can also occur in obese patients, is considered a strong predictor of frailty, disability, and mortality in older persons and is present in 5–13% of elderly persons aged 60–70 years and up to 50% of all octogenarians. In a CHF study, sarcopenia was associated with lower strength, reduced peak oxygen consumption (peak VO2, 1173 ± 433 vs. 1622 ± 456 mL/min), and lower exercise time (7.7 ± 3.8 vs. 10.22 ± 3.0 min, both P < 0.001). Unfortunately, there are only very limited therapy options. Currently, the main intervention remains resistance exercise. Specialized nutritional support may aid the effects of resistance training. Testosterone has significant positive effects on muscle mass and function, and low endogenous testosterone has been described as an independent risk factor in CHF in a study with 618 men (hazard ratio 0.929, P = 0.042). However, the use of testosterone is controversial because of possible side effects. Selective androgen receptor modulators have been developed to overcome these side effects but are not yet available on the market. Further investigational drugs include growth hormone, insulin‐like growth factor 1, and several compounds that target the myostatin pathway. The continuing development of new treatment strategies and compounds for sarcopenia, muscle wasting regardless of CHF, and cardiac cachexia makes this a stimulating research area.

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Activin A induces skeletal muscle catabolism via p38β mitogen‐activated protein kinase

Cited by 64 publications

References 55 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

The systemic activin response to pancreatic cancer: implications for effective cancer cachexia therapy

Skeletal muscle wasting in chronic heart failure

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