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Juha J. Hulmi - One of the best experts on this subject based on the ideXlab platform.

  • systemic blockade of ACVR2B ligands attenuates muscle wasting in ischemic heart failure without compromising cardiac function
    The FASEB Journal, 2020
    Co-Authors: Zoltan Szabo, Juha J. Hulmi, Arja Pasternack, Laura Vainio, Lea Rahtukorpela, Julia Swan, Raisa Serpi, Mika Laitinen, Olli Ritvos
    Abstract:

    : Signaling through activin receptors regulates skeletal muscle mass and activin receptor 2B (ACVR2B) ligands are also suggested to participate in myocardial infarction (MI) pathology in the heart. In this study, we determined the effect of systemic blockade of ACVR2B ligands on cardiac function in experimental MI, and defined its efficacy to revert muscle wasting in ischemic heart failure (HF). Mice were treated with soluble ACVR2B decoy receptor (ACVR2B-Fc) to study its effect on post-MI cardiac remodeling and on later HF. Cardiac function was determined with echocardiography, and myocardium analyzed with histological and biochemical methods for hypertrophy and fibrosis. Pharmacological blockade of ACVR2B ligands did not rescue the heart from ischemic injury or alleviate post-MI remodeling and ischemic HF. Collectively, ACVR2B-Fc did not affect cardiomyocyte hypertrophy, fibrosis, angiogenesis, nor factors associated with cardiac regeneration except modification of certain genes involved in metabolism or cell growth/survival. ACVR2B-Fc, however, was able to reduce skeletal muscle wasting in chronic ischemic HF, accompanied by reduced LC3II as a marker of autophagy and increased mTOR signaling and Cited4 expression as markers of physiological hypertrophy in quadriceps muscle. Our results ascertain pharmacological blockade of ACVR2B ligands as a possible therapy for skeletal muscle wasting in ischemic HF. Pharmacological blockade of ACVR2B ligands preserved myofiber size in ischemic HF, but did not compromise cardiac function nor exacerbate cardiac remodeling after ischemic injury.

  • Muscle and serum metabolomes are dysregulated in colon-26 tumor-bearing mice despite amelioration of cachexia with activin receptor type 2B ligand blockade.
    American Journal of Physiology-endocrinology and Metabolism, 2019
    Co-Authors: Juulia H Lautaoja, Jaakko Hentilä, Olli Ritvos, Tuuli A Nissinen, Maciej Lalowski, Sulin Cheng, Juha J. Hulmi
    Abstract:

    Cancer-associated cachexia reduces survival, which has been attenuated by blocking the activin receptor type 2B (ACVR2B) ligands in mice. The purpose of this study was to unravel the underlying phy...

  • systemic blockade of ACVR2B ligands protects myocardium from acute ischemia reperfusion injury
    Molecular Therapy, 2019
    Co-Authors: Johanna Magga, Juha J. Hulmi, Markus Rasanen, Laura Vainio, Teemu Kilpio, Saija Taponen, Zoltan Szabo, Lea Rahtukorpela, Tarja Alakoski
    Abstract:

    Activin A and myostatin, members of the transforming growth factor (TGF)-β superfamily of secreted factors, are potent negative regulators of muscle growth, but their contribution to myocardial ischemia-reperfusion (IR) injury is not known. The aim of this study was to investigate if activin 2B (ACVR2B) receptor ligands contribute to myocardial IR injury. Mice were treated with soluble ACVR2B decoy receptor (ACVR2B-Fc) and subjected to myocardial ischemia followed by reperfusion for 6 or 24 h. Systemic blockade of ACVR2B ligands by ACVR2B-Fc was protective against cardiac IR injury, as evidenced by reduced infarcted area, apoptosis, and autophagy and better preserved LV systolic function following IR. ACVR2B-Fc modified cardiac metabolism, LV mitochondrial respiration, as well as cardiac phenotype toward physiological hypertrophy. Similar to its protective role in IR injury in vivo, ACVR2B-Fc antagonized SMAD2 signaling and cell death in cardiomyocytes that were subjected to hypoxic stress. ACVR2B ligand myostatin was found to exacerbate hypoxic stress. In addition to acute cardioprotection in ischemia, ACVR2B-Fc provided beneficial effects on cardiac function in prolonged cardiac stress in cardiotoxicity model. By blocking myostatin, ACVR2B-Fc potentially reduces cardiomyocyte death and modifies cardiomyocyte metabolism for hypoxic conditions to protect the heart from IR injury.

  • treating cachexia using soluble ACVR2B improves survival alters mtor localization and attenuates liver and spleen responses
    Journal of Cachexia Sarcopenia and Muscle, 2018
    Co-Authors: Tuuli A Nissinen, Jaakko Hentilä, Olli Ritvos, Fabio Penna, Anita Lampinen, Juulia H Lautaoja, Vasco Fachada, Tanja Holopainen, Riikka Kivela, Juha J. Hulmi
    Abstract:

    BACKGROUND: Cancer 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. METHODS: The 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. RESULTS: Blocking 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. CONCLUSIONS: The 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.

  • prevention of chemotherapy induced cachexia by ACVR2B ligand blocking has different effects on heart and skeletal muscle
    Journal of Cachexia Sarcopenia and Muscle, 2018
    Co-Authors: Juha J. Hulmi, Olli Ritvos, Tuuli A Nissinen, Juulia H Lautaoja, Markus Rasanen, Joni Degerman, Karthik Amudhala Hemanthakumar, Janne T Backman, Mika Silvennoinen, Riikka Kivela
    Abstract:

    BACKGROUND: Toxicity of chemotherapy on skeletal muscles and the heart may significantly contribute to cancer cachexia, mortality, and decreased quality of life. Doxorubicin (DOX) is an effective cytostatic agent, which unfortunately has toxic effects on many healthy tissues. Blocking of activin receptor type IIB (ACVR2B) ligands is an often used strategy to prevent skeletal muscle loss, but its effects on the heart are relatively unknown. METHODS: The effects of DOX treatment with or without pre-treatment with soluble ACVR2B-Fc (sACVR2B-Fc) were investigated. The mice were randomly assigned into one of the three groups: (1) vehicle (PBS)-treated controls, (2) DOX-treated mice (DOX), and (3) DOX-treated mice administered with sACVR2B-Fc during the experiment (DOX + sACVR2B-Fc). DOX was administered with a cumulative dose of 24 mg/kg during 2 weeks to investigate cachexia outcome in the heart and skeletal muscle. To understand similarities and differences between skeletal and cardiac muscles in their responses to chemotherapy, the tissues were collected 20 h after a single DOX (15 mg/kg) injection and analysed with genome-wide transcriptomics and mRNA and protein analyses. The combination group was pre-treated with sACVR2B-Fc 48 h before DOX administration. Major findings were also studied in mice receiving only sACVR2B-Fc. RESULTS: The DOX treatment induced similar (~10%) wasting in skeletal muscle and the heart. However, transcriptional changes in response to DOX were much greater in skeletal muscle. Pathway analysis and unbiased transcription factor analysis showed that p53-p21-REDD1 is the main common pathway activated by DOX in both skeletal and cardiac muscles. These changes were attenuated by blocking ACVR2B ligands especially in skeletal muscle. Tceal7 (3-fold to 5-fold increase), transferrin receptor (1.5-fold increase), and Ccl21 (0.6-fold to 0.9-fold decrease) were identified as novel genes responsive to blocking ACVR2B ligands. Overall, at the transcriptome level, ACVR2B ligand blocking had only minor influence in the heart while it had marked effects in skeletal muscle. The same was also true for the effects on tissue wasting. This may be explained in part by about 18-fold higher gene expression of myostatin in skeletal muscle compared with the heart. CONCLUSIONS: Cardiac and skeletal muscles display similar atrophy after DOX treatment, but the mechanisms for this may differ between the tissues. The present results suggest that p53-p21-REDD1 signalling is the main common DOX-activated pathway in these tissues and that blocking activin receptor ligands attenuates this response, especially in skeletal muscle supporting the overall stronger effects of this treatment in skeletal muscles.

Toril Holien - One of the best experts on this subject based on the ideXlab platform.

  • BMPR2 inhibits activin and BMP signaling via wild-type ALK2.
    Journal of Cell Science, 2018
    Co-Authors: Oddrun Elise Olsen, Hanne Hella, Meenu Sankar, Samah Elsaadi, Glenn Buene, Sagar Ramesh Darvekar, Kristine Misund, Takenobu Katagiri, Petra Knaus, Toril Holien
    Abstract:

    TGF-β/BMP superfamily ligands require heteromeric complexes of type 1 and 2 receptors for ligand dependent downstream signaling. Activin A, a TGF-β superfamily member, inhibits growth of multiple myeloma cells, but the mechanism is unknown. We aimed to clarify how activins affect myeloma cell survival. Activin A activates the transcription factors SMAD2/3 through the ALK4 type 1 receptor, but may also activate SMAD1/5/8 through mutated variants of the type 1 receptor ALK2. We demonstrate that activin A and B activate SMAD1/5/8 in myeloma cells through endogenous wild type ALK2. Knockdown of the type 2 receptor BMPR2 strongly potentiated activin A- and B-induced SMAD1/5/8 activation and subsequent cell death. Furthermore, activity of BMP6, BMP7 or BMP9, which also may signal via ALK2, was potentiated by BMPR2 knockdown. Similar results were seen in HepG2 liver carcinoma cells. We propose that BMPR2 inhibits ALK2-mediated signaling by preventing ALK2 from oligomerizing with the type 2 receptors ACVR2A and ACVR2B, necessary for ALK2 activation by activins and several BMPs. In conclusion, BMPR2 could be explored as a possible target for therapy in patients with multiple myeloma.

  • BMPR2 inhibits activin- and BMP-signaling via wild type ALK2
    bioRxiv, 2017
    Co-Authors: Oddrun Elise Olsen, Hanne Hella, Meenu Sankar, Samah Elsaadi, Glenn Buene, Sagar Ramesh Darvekar, Kristine Misund, Takenobu Katagiri, Toril Holien
    Abstract:

    Activin A is a member of the TGF-β superfamily and activates the transcription factors SMAD2/3 through the ALK4 type 1 receptor. Activin A has also been shown to activate SMAD1/5/8 through mutated variants of the type 1 receptor ALK2. Interestingly, we here show that both activin A and activin B could activate SMAD1/5/8 through endogenous wild type ALK2 in multiple myeloma cells. Knockdown of the type 2 receptor BMPR2 strongly potentiated activin A- and activin B-induced SMAD1/5/8 activation and subsequent cell death. Furthermore, activity of BMP6, BMP7 or BMP9, which also signal via ALK2, was potentiated by BMPR2 knockdown. Similar results were seen in HepG2 liver carcinoma cells. We propose that BMPR2 inhibited ALK2-mediated signaling by preventing ALK2 from oligomerizing with the type 2 receptors ACVR2A and ACVR2B, necessary for ALK2 activation by activins and several BMPs in these cells. In conclusion, BMPR2 could be explored as a possible target for therapy in patients with multiple myeloma.

  • activin a inhibits bmp signaling by binding acvr2a and ACVR2B
    Cell Communication and Signaling, 2015
    Co-Authors: Oddrun Elise Olsen, Karin Fahl Wader, Hanne Hella, Anne K Mylin, Ingemar Turesson, Ingerid Nesthus, Anders Waage, Anders Sundan, Toril Holien
    Abstract:

    Background: Activins are members of the TGF-β family of ligands that have multiple biological functions in embryonic stem cells as well as in differentiated tissue. Serum levels of activin A were found to be elevated in pathological conditions such as cachexia, osteoporosis and cancer. Signaling by activin A through canonical ALK4-ACVR2 receptor complexes activates the transcription factors SMAD2 and SMAD3. Activin A has a strong affinity to type 2 receptors, a feature that they share with some of the bone morphogenetic proteins (BMPs). Activin A is also elevated in myeloma patients with advanced disease and is involved in myeloma bone disease. Results: In this study we investigated effects of activin A binding to receptors that are shared with BMPs using myeloma cell lines with well-characterized BMP-receptor expression and responses. Activin A antagonized BMP-6 and BMP-9, but not BMP-2 and BMP-4. Activin A was able to counteract BMPs that signal through the type 2 receptors ACVR2A and ACVR2B in combination with ALK2, but not BMPs that signal through BMPR2 in combination with ALK3 and ALK6. Conclusions: We propose that one important way that activin A regulates cell behavior is by antagonizing BMP-ACVR2A/ACVR2B/ALK2 signaling.

Oddrun Elise Olsen - One of the best experts on this subject based on the ideXlab platform.

  • BMPR2 inhibits activin and BMP signaling via wild-type ALK2.
    Journal of Cell Science, 2018
    Co-Authors: Oddrun Elise Olsen, Hanne Hella, Meenu Sankar, Samah Elsaadi, Glenn Buene, Sagar Ramesh Darvekar, Kristine Misund, Takenobu Katagiri, Petra Knaus, Toril Holien
    Abstract:

    TGF-β/BMP superfamily ligands require heteromeric complexes of type 1 and 2 receptors for ligand dependent downstream signaling. Activin A, a TGF-β superfamily member, inhibits growth of multiple myeloma cells, but the mechanism is unknown. We aimed to clarify how activins affect myeloma cell survival. Activin A activates the transcription factors SMAD2/3 through the ALK4 type 1 receptor, but may also activate SMAD1/5/8 through mutated variants of the type 1 receptor ALK2. We demonstrate that activin A and B activate SMAD1/5/8 in myeloma cells through endogenous wild type ALK2. Knockdown of the type 2 receptor BMPR2 strongly potentiated activin A- and B-induced SMAD1/5/8 activation and subsequent cell death. Furthermore, activity of BMP6, BMP7 or BMP9, which also may signal via ALK2, was potentiated by BMPR2 knockdown. Similar results were seen in HepG2 liver carcinoma cells. We propose that BMPR2 inhibits ALK2-mediated signaling by preventing ALK2 from oligomerizing with the type 2 receptors ACVR2A and ACVR2B, necessary for ALK2 activation by activins and several BMPs. In conclusion, BMPR2 could be explored as a possible target for therapy in patients with multiple myeloma.

  • BMPR2 inhibits activin- and BMP-signaling via wild type ALK2
    bioRxiv, 2017
    Co-Authors: Oddrun Elise Olsen, Hanne Hella, Meenu Sankar, Samah Elsaadi, Glenn Buene, Sagar Ramesh Darvekar, Kristine Misund, Takenobu Katagiri, Toril Holien
    Abstract:

    Activin A is a member of the TGF-β superfamily and activates the transcription factors SMAD2/3 through the ALK4 type 1 receptor. Activin A has also been shown to activate SMAD1/5/8 through mutated variants of the type 1 receptor ALK2. Interestingly, we here show that both activin A and activin B could activate SMAD1/5/8 through endogenous wild type ALK2 in multiple myeloma cells. Knockdown of the type 2 receptor BMPR2 strongly potentiated activin A- and activin B-induced SMAD1/5/8 activation and subsequent cell death. Furthermore, activity of BMP6, BMP7 or BMP9, which also signal via ALK2, was potentiated by BMPR2 knockdown. Similar results were seen in HepG2 liver carcinoma cells. We propose that BMPR2 inhibited ALK2-mediated signaling by preventing ALK2 from oligomerizing with the type 2 receptors ACVR2A and ACVR2B, necessary for ALK2 activation by activins and several BMPs in these cells. In conclusion, BMPR2 could be explored as a possible target for therapy in patients with multiple myeloma.

  • activin a inhibits bmp signaling by binding acvr2a and ACVR2B
    Cell Communication and Signaling, 2015
    Co-Authors: Oddrun Elise Olsen, Karin Fahl Wader, Hanne Hella, Anne K Mylin, Ingemar Turesson, Ingerid Nesthus, Anders Waage, Anders Sundan, Toril Holien
    Abstract:

    Background: Activins are members of the TGF-β family of ligands that have multiple biological functions in embryonic stem cells as well as in differentiated tissue. Serum levels of activin A were found to be elevated in pathological conditions such as cachexia, osteoporosis and cancer. Signaling by activin A through canonical ALK4-ACVR2 receptor complexes activates the transcription factors SMAD2 and SMAD3. Activin A has a strong affinity to type 2 receptors, a feature that they share with some of the bone morphogenetic proteins (BMPs). Activin A is also elevated in myeloma patients with advanced disease and is involved in myeloma bone disease. Results: In this study we investigated effects of activin A binding to receptors that are shared with BMPs using myeloma cell lines with well-characterized BMP-receptor expression and responses. Activin A antagonized BMP-6 and BMP-9, but not BMP-2 and BMP-4. Activin A was able to counteract BMPs that signal through the type 2 receptors ACVR2A and ACVR2B in combination with ALK2, but not BMPs that signal through BMPR2 in combination with ALK3 and ALK6. Conclusions: We propose that one important way that activin A regulates cell behavior is by antagonizing BMP-ACVR2A/ACVR2B/ALK2 signaling.

Olli Ritvos - One of the best experts on this subject based on the ideXlab platform.

  • systemic blockade of ACVR2B ligands attenuates muscle wasting in ischemic heart failure without compromising cardiac function
    The FASEB Journal, 2020
    Co-Authors: Zoltan Szabo, Juha J. Hulmi, Arja Pasternack, Laura Vainio, Lea Rahtukorpela, Julia Swan, Raisa Serpi, Mika Laitinen, Olli Ritvos
    Abstract:

    : Signaling through activin receptors regulates skeletal muscle mass and activin receptor 2B (ACVR2B) ligands are also suggested to participate in myocardial infarction (MI) pathology in the heart. In this study, we determined the effect of systemic blockade of ACVR2B ligands on cardiac function in experimental MI, and defined its efficacy to revert muscle wasting in ischemic heart failure (HF). Mice were treated with soluble ACVR2B decoy receptor (ACVR2B-Fc) to study its effect on post-MI cardiac remodeling and on later HF. Cardiac function was determined with echocardiography, and myocardium analyzed with histological and biochemical methods for hypertrophy and fibrosis. Pharmacological blockade of ACVR2B ligands did not rescue the heart from ischemic injury or alleviate post-MI remodeling and ischemic HF. Collectively, ACVR2B-Fc did not affect cardiomyocyte hypertrophy, fibrosis, angiogenesis, nor factors associated with cardiac regeneration except modification of certain genes involved in metabolism or cell growth/survival. ACVR2B-Fc, however, was able to reduce skeletal muscle wasting in chronic ischemic HF, accompanied by reduced LC3II as a marker of autophagy and increased mTOR signaling and Cited4 expression as markers of physiological hypertrophy in quadriceps muscle. Our results ascertain pharmacological blockade of ACVR2B ligands as a possible therapy for skeletal muscle wasting in ischemic HF. Pharmacological blockade of ACVR2B ligands preserved myofiber size in ischemic HF, but did not compromise cardiac function nor exacerbate cardiac remodeling after ischemic injury.

  • Muscle and serum metabolomes are dysregulated in colon-26 tumor-bearing mice despite amelioration of cachexia with activin receptor type 2B ligand blockade.
    American Journal of Physiology-endocrinology and Metabolism, 2019
    Co-Authors: Juulia H Lautaoja, Jaakko Hentilä, Olli Ritvos, Tuuli A Nissinen, Maciej Lalowski, Sulin Cheng, Juha J. Hulmi
    Abstract:

    Cancer-associated cachexia reduces survival, which has been attenuated by blocking the activin receptor type 2B (ACVR2B) ligands in mice. The purpose of this study was to unravel the underlying phy...

  • treating cachexia using soluble ACVR2B improves survival alters mtor localization and attenuates liver and spleen responses
    Journal of Cachexia Sarcopenia and Muscle, 2018
    Co-Authors: Tuuli A Nissinen, Jaakko Hentilä, Olli Ritvos, Fabio Penna, Anita Lampinen, Juulia H Lautaoja, Vasco Fachada, Tanja Holopainen, Riikka Kivela, Juha J. Hulmi
    Abstract:

    BACKGROUND: Cancer 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. METHODS: The 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. RESULTS: Blocking 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. CONCLUSIONS: The 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.

  • prevention of chemotherapy induced cachexia by ACVR2B ligand blocking has different effects on heart and skeletal muscle
    Journal of Cachexia Sarcopenia and Muscle, 2018
    Co-Authors: Juha J. Hulmi, Olli Ritvos, Tuuli A Nissinen, Juulia H Lautaoja, Markus Rasanen, Joni Degerman, Karthik Amudhala Hemanthakumar, Janne T Backman, Mika Silvennoinen, Riikka Kivela
    Abstract:

    BACKGROUND: Toxicity of chemotherapy on skeletal muscles and the heart may significantly contribute to cancer cachexia, mortality, and decreased quality of life. Doxorubicin (DOX) is an effective cytostatic agent, which unfortunately has toxic effects on many healthy tissues. Blocking of activin receptor type IIB (ACVR2B) ligands is an often used strategy to prevent skeletal muscle loss, but its effects on the heart are relatively unknown. METHODS: The effects of DOX treatment with or without pre-treatment with soluble ACVR2B-Fc (sACVR2B-Fc) were investigated. The mice were randomly assigned into one of the three groups: (1) vehicle (PBS)-treated controls, (2) DOX-treated mice (DOX), and (3) DOX-treated mice administered with sACVR2B-Fc during the experiment (DOX + sACVR2B-Fc). DOX was administered with a cumulative dose of 24 mg/kg during 2 weeks to investigate cachexia outcome in the heart and skeletal muscle. To understand similarities and differences between skeletal and cardiac muscles in their responses to chemotherapy, the tissues were collected 20 h after a single DOX (15 mg/kg) injection and analysed with genome-wide transcriptomics and mRNA and protein analyses. The combination group was pre-treated with sACVR2B-Fc 48 h before DOX administration. Major findings were also studied in mice receiving only sACVR2B-Fc. RESULTS: The DOX treatment induced similar (~10%) wasting in skeletal muscle and the heart. However, transcriptional changes in response to DOX were much greater in skeletal muscle. Pathway analysis and unbiased transcription factor analysis showed that p53-p21-REDD1 is the main common pathway activated by DOX in both skeletal and cardiac muscles. These changes were attenuated by blocking ACVR2B ligands especially in skeletal muscle. Tceal7 (3-fold to 5-fold increase), transferrin receptor (1.5-fold increase), and Ccl21 (0.6-fold to 0.9-fold decrease) were identified as novel genes responsive to blocking ACVR2B ligands. Overall, at the transcriptome level, ACVR2B ligand blocking had only minor influence in the heart while it had marked effects in skeletal muscle. The same was also true for the effects on tissue wasting. This may be explained in part by about 18-fold higher gene expression of myostatin in skeletal muscle compared with the heart. CONCLUSIONS: Cardiac and skeletal muscles display similar atrophy after DOX treatment, but the mechanisms for this may differ between the tissues. The present results suggest that p53-p21-REDD1 signalling is the main common DOX-activated pathway in these tissues and that blocking activin receptor ligands attenuates this response, especially in skeletal muscle supporting the overall stronger effects of this treatment in skeletal muscles.

  • systemic blockade of ACVR2B ligands prevents chemotherapy induced muscle wasting by restoring muscle protein synthesis without affecting oxidative capacity or atrogenes
    Scientific Reports, 2016
    Co-Authors: Tuuli A Nissinen, Olli Ritvos, Riikka Kivela, Markus Rasanen, Joni Degerman, A R Poikonen, S O A Koskinen, Eero Mervaala, Arja Pasternack, Juha J. Hulmi
    Abstract:

    : Doxorubicin is a widely used and effective chemotherapy drug. However, cardiac and skeletal muscle toxicity of doxorubicin limits its use. Inhibiting myostatin/activin signalling can prevent muscle atrophy, but its effects in chemotherapy-induced muscle wasting are unknown. In the present study we investigated the effects of doxorubicin administration alone or combined with activin receptor ligand pathway blockade by soluble activin receptor IIB (sACVR2B-Fc). Doxorubicin administration decreased body mass, muscle size and bone mineral density/content in mice. However, these effects were prevented by sACVR2B-Fc administration. Unlike in many other wasting situations, doxorubicin induced muscle atrophy without markedly increasing typical atrogenes or protein degradation pathways. Instead, doxorubicin decreased muscle protein synthesis which was completely restored by sACVR2B-Fc. Doxorubicin administration also resulted in impaired running performance without effects on skeletal muscle mitochondrial capacity/function or capillary density. Running performance and mitochondrial function were unaltered by sACVR2B-Fc administration. Tumour experiment using Lewis lung carcinoma cells demonstrated that sACVR2B-Fc decreased the cachectic effects of chemotherapy without affecting tumour growth. These results demonstrate that blocking ACVR2B signalling may be a promising strategy to counteract chemotherapy-induced muscle wasting without damage to skeletal muscle oxidative capacity or cancer treatment.

Feng Tang - One of the best experts on this subject based on the ideXlab platform.

  • microrna 194 protects against chronic hepatitis b related liver damage by promoting hepatocyte growth via ACVR2B
    Journal of Cellular and Molecular Medicine, 2018
    Co-Authors: Pan Zhao, Jie Hu, Jiming Zhang, Zhongwen Zhou, Jingmin Zhao, Feng Tang
    Abstract:

    : Persistent infection with the hepatitis B virus leads to liver cirrhosis and hepatocellular carcinoma. MicroRNAs (miRNAs) play an important role in a variety of biological processes; however, the role of miRNAs in chronic hepatitis B (CHB)-induced liver damage remains poorly understood. Here, we investigated the role of miRNAs in CHB-related liver damage. Microarray analysis of the expression of miRNAs in 22 CHB patients and 33 healthy individuals identified miR-194 as one of six differentially expressed miRNAs. miR-194 was up-regulated in correlation with increased liver damage in the plasma or liver tissues of CHB patients. In mice subjected to 2/3 partial hepatectomy, miR-194 was up-regulated in liver tissues in correlation with hepatocyte growth and in parallel with the down-regulation of the activin receptor ACVR2B. Overexpression of miR-194 in human liver HL7702 cells down-regulated ACVR2B mRNA and protein expression, promoted cell proliferation, acceleratedG1 to S cell cycle transition, and inhibited apoptosis, whereas knockdown of miR-194 had the opposite effects. Luciferase reporter assays confirmed that ACVR2B is a direct target of miR-194, and overexpression of ACVR2B significantly repressed cell proliferation and G1 to S phase transition and induced cell apoptosis. ACVR2B overexpression abolished the effect of miR-194, indicating that miR-194 promotes hepatocyte proliferation and inhibits apoptosis by down-regulating ACVR2B. Taken together, these results indicate that miR-194 plays a crucial role in hepatocyte proliferation and liver regeneration by targeting ACVR2B and may represent a novel therapeutic target for the treatment of CHB-related liver damage.

  • MicroRNA‐194 protects against chronic hepatitis B‐related liver damage by promoting hepatocyte growth via ACVR2B
    Journal of Cellular and Molecular Medicine, 2018
    Co-Authors: Pan Zhao, Jie Hu, Jiming Zhang, Zhongwen Zhou, Jingmin Zhao, Feng Tang
    Abstract:

    : Persistent infection with the hepatitis B virus leads to liver cirrhosis and hepatocellular carcinoma. MicroRNAs (miRNAs) play an important role in a variety of biological processes; however, the role of miRNAs in chronic hepatitis B (CHB)-induced liver damage remains poorly understood. Here, we investigated the role of miRNAs in CHB-related liver damage. Microarray analysis of the expression of miRNAs in 22 CHB patients and 33 healthy individuals identified miR-194 as one of six differentially expressed miRNAs. miR-194 was up-regulated in correlation with increased liver damage in the plasma or liver tissues of CHB patients. In mice subjected to 2/3 partial hepatectomy, miR-194 was up-regulated in liver tissues in correlation with hepatocyte growth and in parallel with the down-regulation of the activin receptor ACVR2B. Overexpression of miR-194 in human liver HL7702 cells down-regulated ACVR2B mRNA and protein expression, promoted cell proliferation, acceleratedG1 to S cell cycle transition, and inhibited apoptosis, whereas knockdown of miR-194 had the opposite effects. Luciferase reporter assays confirmed that ACVR2B is a direct target of miR-194, and overexpression of ACVR2B significantly repressed cell proliferation and G1 to S phase transition and induced cell apoptosis. ACVR2B overexpression abolished the effect of miR-194, indicating that miR-194 promotes hepatocyte proliferation and inhibits apoptosis by down-regulating ACVR2B. Taken together, these results indicate that miR-194 plays a crucial role in hepatocyte proliferation and liver regeneration by targeting ACVR2B and may represent a novel therapeutic target for the treatment of CHB-related liver damage.