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1. Neutralizing antibodies after the third COVID-19 vaccination in healthcare workers with or without breakthrough infection

Author

Reinholm, Arttu, Maljanen, Sari, Jalkanen, Pinja, Altan, Eda, Tauriainen, Sisko, Belik, Milja, Skön, Marika, Haveri, Anu, Österlund, Pamela, Iakubovskaia, Alina, Pasternack, Arja, Naves, Rauno A., Ritvos, Olli, Miettinen, Simo, K. Häkkinen, Hanni, Ivaska, Lauri, Tähtinen, Paula A., Lempainen, Johanna, Kantele, Anu, Kakkola, Laura, Julkunen, Ilkka, and Kolehmainen, Pekka

Published
2024
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4. Intranasal trimeric sherpabody inhibits SARS-CoV-2 including recent immunoevasive Omicron subvariants

Author

Mäkelä, Anna R., Uğurlu, Hasan, Hannula, Liina, Kant, Ravi, Salminen, Petja, Fagerlund, Riku, Mäki, Sanna, Haveri, Anu, Strandin, Tomas, Kareinen, Lauri, Hepojoki, Jussi, Kuivanen, Suvi, Levanov, Lev, Pasternack, Arja, Naves, Rauno A., Ritvos, Olli, Österlund, Pamela, Sironen, Tarja, Vapalahti, Olli, Kipar, Anja, Huiskonen, Juha T., Rissanen, Ilona, and Saksela, Kalle

Published
2023
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7. Long-term COVID-19 vaccine- and Omicron infection-induced humoral and cell-mediated immunity.

Author

Belik, Milja, Reinholm, Arttu, Kolehmainen, Pekka, Heroum, Jemna, Maljanen, Sari, Altan, Eda, Österlund, Pamela, Laine, Larissa, Ritvos, Olli, Pasternack, Arja, Naves, Rauno A., Iakubovskaia, Alina, Barkoff, Alex-Mikael, He, Qiushui, Lempainen, Johanna, Tähtinen, Paula A., Ivaska, Lauri, Jalkanen, Pinja, Julkunen, Ilkka, and Kakkola, Laura

Subjects
MEDICAL personnel, SARS-CoV-2 Omicron variant, CELLULAR immunity, BOOSTER vaccines, HUMORAL immunity
Abstract

Introduction: Mutations occurring in the spike (S) protein of SARS-CoV-2 enables the virus to evade COVID-19 vaccine- and infection-induced immunity. Methods: Here we provide a comprehensive analysis of humoral and cell-mediated immunity in 111 healthcare workers who received three or four vaccine doses and were followed up to 12 and 6 months, respectively, after the last vaccine dose. Omicron breakthrough infection occurred in 71% of the vaccinees, enabling evaluation of vaccine- and vaccine/infection-induced hybrid immunity. Results: Neutralizing antibodies were the highest against the ancestral D614G and were sequentially reduced against the Omicron variants BA.2, BA.5 and XBB.1.5. S1-specific IgG and neutralizing antibody levels were significantly higher in infected than in uninfected vaccinees, and the fourth vaccine dose in combination with a breakthrough infection resulted in high neutralizing antibody levels against all variants. T cell-mediated immunity, instead, was well retained already after two vaccine doses, and was not significantly strengthened by additional booster vaccine doses or Omicron breakthrough infections. Discussion: While humoral immunity is sensitive to mutations in the S protein and thus declined rapidly, the cell-mediated immunity is durable to antigenic variation, which may explain the good efficacy of COVID-19 vaccines against a severe disease. [ABSTRACT FROM AUTHOR]

Published
2024
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8. Improved health by combining dietary restriction and promoting muscle growth in DNA repair‐deficient progeroid mice.

Author

Vermeij, Wilbert P., Alyodawi, Khalid, van Galen, Ivar, von der Heide, Jennie L., Birkisdóttir, María B., van't Sant, Lisanne J., Ozinga, Rutger A., Komninos, Daphne S.J., Smit, Kimberly, Rijksen, Yvonne M.A., Brandt, Renata M.C., Barnhoorn, Sander, Jaarsma, Dick, Vaiyapuri, Sathivel, Ritvos, Olli, Huber, Tobias B., Kretz, Oliver, and Patel, Ketan

Published
2024
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10. Comparative analysis of COVID-19 vaccine responses and third booster dose-induced neutralizing antibodies against Delta and Omicron variants

Author

Belik, Milja, Jalkanen, Pinja, Lundberg, Rickard, Reinholm, Arttu, Laine, Larissa, Väisänen, Elina, Skön, Marika, Tähtinen, Paula A., Ivaska, Lauri, Pakkanen, Sari H., Häkkinen, Hanni K., Ortamo, Eeva, Pasternack, Arja, Ritvos, Mikael A., Naves, Rauno A., Miettinen, Simo, Sironen, Tarja, Vapalahti, Olli, Ritvos, Olli, Österlund, Pamela, Kantele, Anu, Lempainen, Johanna, Kakkola, Laura, Kolehmainen, Pekka, and Julkunen, Ilkka

Published
2022
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15. COVID-19 mRNA vaccine induced antibody responses against three SARS-CoV-2 variants

Author

Jalkanen, Pinja, Kolehmainen, Pekka, Häkkinen, Hanni K., Huttunen, Moona, Tähtinen, Paula A., Lundberg, Rickard, Maljanen, Sari, Reinholm, Arttu, Tauriainen, Sisko, Pakkanen, Sari H., Levonen, Iris, Nousiainen, Arttu, Miller, Taru, Välimaa, Hanna, Ivaska, Lauri, Pasternack, Arja, Naves, Rauno, Ritvos, Olli, Österlund, Pamela, Kuivanen, Suvi, Smura, Teemu, Hepojoki, Jussi, Vapalahti, Olli, Lempainen, Johanna, Kakkola, Laura, Kantele, Anu, and Julkunen, Ilkka

Published
2021
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16. Orphan GPR116 mediates the insulin sensitizing effects of the hepatokine FNDC4 in adipose tissue

Author

Georgiadi, Anastasia, Lopez-Salazar, Valeria, Merahbi, Rabih El-, Karikari, Rhoda Anane, Ma, Xiaochuan, Mourão, André, Klepac, Katarina, Bühler, Lea, Alfaro, Ana Jimena, Kaczmarek, Isabell, Linford, Adam, Bosma, Madeleen, Shilkova, Olga, Ritvos, Olli, Nakamura, Nobuhiro, Hirose, Shigehisa, Lassi, Maximilian, Teperino, Raffaele, Machado, Juliano, Scheideler, Marcel, Dietrich, Arne, Geerlof, Arie, Feuchtinger, Annette, Blutke, Andreas, Fischer, Katrin, Müller, Timo Dirk, Kessler, Katharina, Schöneberg, Torsten, Thor, Doreen, Hornemann, Silke, Kruse, Michael, Nawroth, Peter, Pivovarova-Ramich, Olga, Pfeiffer, Andreas Friedrich Hermann, Sattler, Michael, Blüher, Matthias, and Herzig, Stephan

Published
2021
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20. Treadmill running and mechanical overloading improved the strength of the plantaris muscle in the dystrophin‐desmin double knockout (DKO) mouse.

Author

Moutachi, Dylan, Hyzewicz, Janek, Roy, Pauline, Lemaitre, Mégane, Bachasson, Damien, Amthor, Helge, Ritvos, Olli, Li, Zhenlin, Furling, Denis, Agbulut, Onnik, and Ferry, Arnaud

Subjects
TREADMILL exercise, SKELETAL muscle, DUCHENNE muscular dystrophy, SEDENTARY behavior, DYSTROPHIN, ADULTS, HIGHER education
Abstract

Limited knowledge exists regarding the chronic effect of muscular exercise on muscle function in a murine model of severe Duchenne muscular dystrophy (DMD). Here we determined the effects of 1 month of voluntary wheel running (WR), 1 month of enforced treadmill running (TR) and 1 month of mechanical overloading resulting from the removal of the synergic muscles (OVL) in mice lacking both dystrophin and desmin (DKO). Additionally, we examined the effect of activin receptor administration (AR). DKO mice, displaying severe muscle weakness, atrophy and greater susceptibility to contraction‐induced functional loss, were exercised or treated with AR at 1 month of age and in situ force production of lower leg muscle was measured at the age of 2 months. We found that TR and OVL increased absolute maximal force and the rate of force development of the plantaris muscle in DKO mice. In contrast, those of the tibialis anterior (TA) muscle remained unaffected by TR and WR. Furthermore, the effects of TR and OVL on plantaris muscle function in DKO mice closely resembled those in mdx mice, a less severe murine DMD model. AR also improved absolute maximal force and the rate of force development of the TA muscle in DKO mice. In conclusion, exercise training improved plantaris muscle weakness in severely affected dystrophic mice. Consequently, these preclinical results may contribute to fostering further investigations aimed at assessing the potential benefits of exercise for DMD patients, particularly resistance training involving a low number of intense muscle contractions. Key points: Very little is known about the effects of exercise training in a murine model of severe Duchenne muscular dystrophy (DMD). One reason is that it is feared that chronic muscular exercise, particularly that involving intense muscle contractions, could exacerbate the disease.In DKO mice lacking both dystrophin and desmin, characterized by severe lower leg muscle weakness, atrophy and fragility in comparison to the less severe DMD mdx model, we found that enforced treadmill running improved absolute maximal force of the plantaris muscle, while that of tibialis anterior muscle remained unaffected by both enforced treadmill and voluntary wheel running.Furthermore, mechanical overloading, a non‐physiological model of chronic resistance exercise, reversed plantaris muscle weakness.Consequently, our findings may have the potential to alleviate concerns and pave the way for exploring the prescription of endurance and resistance training as a viable therapeutic approach for the treatment of dystrophic patients. Additionally, such interventions may serve in mitigating the pathophysiological mechanisms induced by physical inactivity. [ABSTRACT FROM AUTHOR]

Published
2024
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23. Pro-cachectic factors link experimental and human chronic kidney disease to skeletal muscle wasting programs

Author

Solagna, Francesca, Tezze, Caterina, Lindenmeyer, Maja T., Lu, Shun, Wu, Guochao, Liu, Shuya, Zhao, Yu, Mitchell, Robert, Meyer, Charlotte, Omairi, Saleh, Kilic, Temel, Paolini, Andrea, Ritvos, Olli, Pasternack, Arja, Matsakas, Antonios, Kylies, Dominik, Wiesch, Julian Schulze zur, Turner, Jan-Eric, Wanner, Nicola, Nair, Viji, Eichinger, Felix, Menon, Rajasree, Martin, Ina V., Klinkhammer, Barbara M., Hoxha, Elion, Cohen, Clemens D., Tharaux, Pierre-Louis, Boor, Peter, Ostendorf, Tammo, Kretzler, Matthias, Sandri, Marco, Kretz, Oliver, Puelles, Victor G., Patel, Ketan, and Huber, Tobias B.

Subjects
Complications and side effects, Physiological aspects, Models, Development and progression, Risk factors, Health aspects, Activins -- Physiological aspects -- Health aspects, Wasting syndrome -- Risk factors -- Development and progression -- Models, Cachexia -- Risk factors -- Complications and side effects -- Models, Chronic kidney failure -- Complications and side effects -- Models
Abstract

Introduction Chronic kidney disease (CKD) affects approximately 10%-15% of the world's population (1) and represents a state of progressive and irreversible loss of kidney function (2). Interestingly, two-thirds of adults [...], Skeletal muscle wasting is commonly associated with chronic kidney disease (CKD), resulting in increased morbidity and mortality. However, the link between kidney and muscle function remains poorly understood. Here, we took a complementary interorgan approach to investigate skeletal muscle wasting in CKD. We identified increased production and elevated blood levels of soluble pro-cachectic factors, including activin A, directly linking experimental and human CKD to skeletal muscle wasting programs. Single-cell sequencing data identified the expression of activin A in specific kidney cell populations of fibroblasts and cells of the juxtaglomerular apparatus. We propose that persistent and increased kidney production of procachectic factors, combined with a lack of kidney clearance, facilitates a vicious kidney/muscle signaling cycle, leading to exacerbated blood accumulation and, thereby, skeletal muscle wasting. Systemic pharmacological blockade of activin A using soluble activin receptor type IIB ligand trap as well as muscle-specific adeno-associated virus-mediated downregulation of its receptor ACVR2A/B prevented muscle wasting in different mouse models of experimental CKD, suggesting that activin A is a key factor in CKD-induced cachexia. In summary, we uncovered a crosstalk between kidney and muscle and propose modulation of activin signaling as a potential therapeutic strategy for skeletal muscle wasting in CKD.

Published
2021
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25. Intranasal trimeric sherpabody inhibits SARS-CoV-2 including recent immunoevasive Omicron subvariants

Author

Mäkelä, Anna R, Uğurlu, Hasan; https://orcid.org/0000-0002-3849-7847, Hannula, Liina, Kant, Ravi; https://orcid.org/0000-0003-3878-9775, Salminen, Petja, Fagerlund, Riku, Mäki, Sanna, Haveri, Anu; https://orcid.org/0000-0003-4620-7536, Strandin, Tomas; https://orcid.org/0000-0002-2454-7479, Kareinen, Lauri; https://orcid.org/0000-0003-2525-7817, Hepojoki, Jussi; https://orcid.org/0000-0001-5699-214X, Kuivanen, Suvi; https://orcid.org/0000-0002-2347-5397, Levanov, Lev, Pasternack, Arja; https://orcid.org/0000-0002-6088-4245, Naves, Rauno A, Ritvos, Olli, Österlund, Pamela; https://orcid.org/0000-0002-2229-6661, Sironen, Tarja; https://orcid.org/0000-0002-2344-2755, Vapalahti, Olli; https://orcid.org/0000-0003-2270-6824, Kipar, Anja; https://orcid.org/0000-0001-7289-3459, Huiskonen, Juha T; https://orcid.org/0000-0002-0348-7323, Rissanen, Ilona; https://orcid.org/0000-0003-4937-1825, Saksela, Kalle; https://orcid.org/0000-0003-0827-122X, Mäkelä, Anna R, Uğurlu, Hasan; https://orcid.org/0000-0002-3849-7847, Hannula, Liina, Kant, Ravi; https://orcid.org/0000-0003-3878-9775, Salminen, Petja, Fagerlund, Riku, Mäki, Sanna, Haveri, Anu; https://orcid.org/0000-0003-4620-7536, Strandin, Tomas; https://orcid.org/0000-0002-2454-7479, Kareinen, Lauri; https://orcid.org/0000-0003-2525-7817, Hepojoki, Jussi; https://orcid.org/0000-0001-5699-214X, Kuivanen, Suvi; https://orcid.org/0000-0002-2347-5397, Levanov, Lev, Pasternack, Arja; https://orcid.org/0000-0002-6088-4245, Naves, Rauno A, Ritvos, Olli, Österlund, Pamela; https://orcid.org/0000-0002-2229-6661, Sironen, Tarja; https://orcid.org/0000-0002-2344-2755, Vapalahti, Olli; https://orcid.org/0000-0003-2270-6824, Kipar, Anja; https://orcid.org/0000-0001-7289-3459, Huiskonen, Juha T; https://orcid.org/0000-0002-0348-7323, Rissanen, Ilona; https://orcid.org/0000-0003-4937-1825, and Saksela, Kalle; https://orcid.org/0000-0003-0827-122X

Abstract

The emergence of increasingly immunoevasive SARS-CoV-2 variants emphasizes the need for prophylactic strategies to complement vaccination in fighting the COVID-19 pandemic. Intranasal administration of neutralizing antibodies has shown encouraging protective potential but there remains a need for SARS-CoV-2 blocking agents that are less vulnerable to mutational viral variation and more economical to produce in large scale. Here we describe TriSb92, a highly manufacturable and stable trimeric antibody-mimetic sherpabody targeted against a conserved region of the viral spike glycoprotein. TriSb92 potently neutralizes SARS-CoV-2, including the latest Omicron variants like BF.7, XBB, and BQ.1.1. In female Balb/c mice intranasal administration of just 5 or 50 micrograms of TriSb92 as early as 8 h before but also 4 h after SARS-CoV-2 challenge can protect from infection. Cryo-EM and biochemical studies reveal triggering of a conformational shift in the spike trimer as the inhibitory mechanism of TriSb92. The potency and robust biochemical properties of TriSb92 together with its resistance against viral sequence evolution suggest that TriSb92 could be useful as a nasal spray for protecting susceptible individuals from SARS-CoV-2 infection.

Published
2023

27. Supplementary Material & figure legends from Oncogene-Induced Senescence Limits the Progression of Pancreatic Neoplasia through Production of Activin A

Author

Zhao, Yajie, primary, Wu, Zhichong, primary, Chanal, Marie, primary, Guillaumond, Fabienne, primary, Goehrig, Delphine, primary, Bachy, Sophie, primary, Principe, Moitza, primary, Ziverec, Audrey, primary, Flaman, Jean-Michel, primary, Collin, Guillaume, primary, Tomasini, Richard, primary, Pasternack, Arja, primary, Ritvos, Olli, primary, Vasseur, Sophie, primary, Bernard, David, primary, Hennino, Ana, primary, and Bertolino, Philippe, primary

Published
2023
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28. Supplementary Data from Oncogene-Induced Senescence Limits the Progression of Pancreatic Neoplasia through Production of Activin A

Author

Zhao, Yajie, primary, Wu, Zhichong, primary, Chanal, Marie, primary, Guillaumond, Fabienne, primary, Goehrig, Delphine, primary, Bachy, Sophie, primary, Principe, Moitza, primary, Ziverec, Audrey, primary, Flaman, Jean-Michel, primary, Collin, Guillaume, primary, Tomasini, Richard, primary, Pasternack, Arja, primary, Ritvos, Olli, primary, Vasseur, Sophie, primary, Bernard, David, primary, Hennino, Ana, primary, and Bertolino, Philippe, primary

Published
2023
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35. Coronavirus spike protein-specific antibodies indicate frequent infections and reinfections in infancy and among BNT162b2-vaccinated healthcare workers

Author

Kolehmainen, Pekka, primary, Huttunen, Moona, additional, Iakubovskaia, Alina, additional, Maljanen, Sari, additional, Tauriainen, Sisko, additional, Yatkin, Emrah, additional, Pasternack, Arja, additional, Naves, Rauno, additional, Toivonen, Laura, additional, Tähtinen, Paula, additional, Ivaska, Lauri, additional, Lempainen, Johanna, additional, Peltola, Ville, additional, Waris, Matti, additional, Kakkola, Laura, additional, Ritvos, Olli, additional, and Julkunen, Ilkka, additional

Published
2022
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36. Coordinated activation of TGF-β and BMP pathways promotes autophagy and limits liver injury after acetaminophen intoxication

Author

Stavropoulos, Athanasios, primary, Divolis, Georgios, additional, Manioudaki, Maria, additional, Gavriil, Ariana, additional, Kloukina, Ismini, additional, Perrea, Despina N., additional, Sountoulidis, Alexandros, additional, Ford, Ethan, additional, Doulou, Athanasia, additional, Apostolidou, Anastasia, additional, Katsantoni, Elena, additional, Ritvos, Olli, additional, Germanidis, Georgios, additional, Xilouri, Maria, additional, and Sideras, Paschalis, additional

Published
2022
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37. Directly immersible silicon photonic probes : Application to rapid SARS-CoV-2 serological testing br

Author

Angelopoulou, Michailia, Makarona, Eleni, Salapatas, Alexandros, Misiakos, Konstantinos, Synolaki, Evgenia, Ioannidis, Anastasios, Chatzipanagiotou, Stylianos, Ritvos, Mikael A., Pasternack, Arja, Ritvos, Olli, Petrou, Panagiota S., Kakabakos, Sotirios E., Angelopoulou, Michailia, Makarona, Eleni, Salapatas, Alexandros, Misiakos, Konstantinos, Synolaki, Evgenia, Ioannidis, Anastasios, Chatzipanagiotou, Stylianos, Ritvos, Mikael A., Pasternack, Arja, Ritvos, Olli, Petrou, Panagiota S., and Kakabakos, Sotirios E.

Abstract

Silicon photonic probes based on broad-band Mach-Zehnder interferometry are explored for the first time as directly immersible immunosensors alleviating the need for microfluidics and pumps. Each probe includes two U- shaped waveguides allowing light in- and out-coupling from the same chip side through a bifurcated fiber and a mechanical coupler. At the opposite chip side, two Mach-Zehnder interferometers (MZI) are located enabling real-time monitoring of binding reactions by immersion of this chip side into a sample. The sensing arm windows of the two MZIs have different length resulting in two distinct peaks in the Fourier domain, the phase shift of which can be monitored independently through Fast Fourier Transform of the output spectrum. The photonic probes analytical potential was demonstrated through detection of antibodies against SARS-CoV-2 in human serum samples. For this, one MZI was functionalized with the Receptor Binding Domain (RBD) of SARS-CoV-2 Spike 1 protein, and the other with bovine serum albumin to serve as reference. The biofunctionalized probes were immersed for 10 min in human serum sample and then for 5 min in goat anti-human IgG Fc specific antibody solution. Using a humanized rat antibody against SARS-CoV-2 RBD, a detection limit of 20 ng/mL was determined. Analysis of human serum samples indicated that the proposed sensor discriminated completely non- infected/non-vaccinated from vaccinated individuals, and the antibodies levels determined correlated well with those determined in the same samples by ELISA. These results demonstrated the potential of the proposed sensor to serve as an efficient tool for expeditious point-of-care testing, QC 20220906

Published
2022
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40. Comparative analysis of BNT162b2, mRNA-1273 and ChAdOx1 COVID-19 vaccine induced antibody responses and the 3rd BNT162b2 vaccine induced neutralizing antibodies against Delta and Omicron variants

Author

Belik, Milja, primary, Jalkanen, Pinja, additional, Lundberg, Rickard, additional, Reinholm, Arttu, additional, Laine, Larissa, additional, Väisänen, Elina, additional, Skön, Marika, additional, Tähtinen, Paula, additional, Ivaska, Lauri, additional, Pakkanen, Sari, additional, Häkkinen, Hanni, additional, Ortamo, Eeva, additional, Pasternack, Arja, additional, Ritvos, Mikael, additional, Naves, Rauno, additional, Miettinen, Simo, additional, Sironen, Tarja, additional, Vapalathti, Olli, additional, Ritvos, Olli, additional, Osterlund, Pamela, additional, Kantele, Anu, additional, Lempainen, Johanna, additional, Kakkola, Laura, additional, Kolehmainen, Pekka, additional, and Julkunen, Ilkka, additional

Published
2022
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41. Intranasal inhibitor broadly blocks SARS-CoV-2 including recent highly immunoevasive Omicron subvariants

Author

Mäkelä, Anna R., primary, Uğurlu, Hasan, additional, Hannula, Liina, additional, Kant, Ravi, additional, Salminen, Petja, additional, Fagerlund, Riku, additional, Mäki, Sanna, additional, Haveri, Anu, additional, Strandin, Tomas, additional, Kareinen, Lauri, additional, Hepojoki, Jussi, additional, Kuivanen, Suvi, additional, Levanov, Lev, additional, Pasternack, Arja, additional, Naves, Rauno A., additional, Ritvos, Olli, additional, Österlund, Pamela, additional, Sironen, Tarja, additional, Vapalahti, Olli, additional, Kipar, Anja, additional, Huiskonen, Juha T., additional, Rissanen, Ilona, additional, and Saksela, Kalle, additional

Published
2021
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42. Intranasal inhibitor blocks omicron and other variants of SARS-CoV-2

Author

Mäkelä, Anna R., primary, Uğurlu, Hasan, additional, Hannula, Liina, additional, Salminen, Petja, additional, Kant, Ravi, additional, Fagerlund, Riku, additional, Haveri, Anu, additional, Strandin, Tomas, additional, Kareinen, Lauri, additional, Hepojoki, Jussi, additional, Levanov, Lev, additional, Pasternack, Arja, additional, Naves, Rauno A., additional, Ritvos, Olli, additional, Österlund, Pamela, additional, Sironen, Tarja, additional, Vapalahti, Olli, additional, Kipar, Anja, additional, Huiskonen, Juha T., additional, Rissanen, Ilona, additional, and Saksela, Kalle, additional

Published
2021
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43. Regulation of Angiopoietin-Like Proteins (ANGPTLs) 3 and 8 by Insulin

Author

Nidhina Haridas, P. A., Soronen, Jarkko, Sädevirta, Sanja, Mysore, Raghavendra, Quagliarini, Fabiana, Pasternack, Arja, Metso, Jari, Perttilä, Julia, Leivonen, Marja, Smas, Cynthia M., Fischer-Posovszky, Pamela, Wabitsch, Martin, Ehnholm, Christian, Ritvos, Olli, Jauhiainen, Matti, Olkkonen, Vesa M., and Yki-Järvinen, Hannele

Published
2015

46. A muscle growth promoting treatment based on the attenuation of activin/myostatin signalling in young mice results in long-term testicular abnormalities

Author

Vaughan, Danielle, Mitchell, Robert, Kretz, Oliver, Chambers, David, Lalowski, Maciej, Amthor, Helge, Ritvos, Olli, Pasternack, Arja, Matsakas, Antonios, Vaiyapuri, Sakthi, Huber, Tobias B., Denecke, Bernd, Mukherjee, Abir, Widera, Darius, and Patel, Ketan

Abstract

Activin/Myostatin signalling acts to induce skeletal muscle atrophy in adult mammals by inhibiting protein synthesis as well as promoting protein and organelle turnover. Numerous strategies have been successfully developed to attenuate the signalling properties of these molecules which result in augmenting muscle growth. However, these molecules, in particular Activin, play major roles in tissue homeostasis in numerous organs of the mammalian body. We have recently shown that while the attenuation of Activin/Myostatin results in robust muscle growth, it also has detrimental impact on the testis. Here, we aimed to discover the long-term consequences of a brief period of exposure to molecules that promote muscle on the testis.\ud \ud We demonstrate that muscle hypertrophy promoted by a soluble Activin Type IIB ligand trap (sActRIIB) is a short-lived phenomenon. In stark contrast, short term treatment with sActRIIB results in immediate impact on the testis which persists after the sessions of the intervention. Gene array analysis identifies an expansion in aberrant gene expression over time in the testis initiated by a brief exposure to muscle growth promoting molecules. The impact on the testis results in decreased organ size as well as quantitative and qualitative impact on sperm. Finally, we have used a drug-repurposing strategy to exploit the gene expression data to identify a compound N6-methyladenosine, that may protect the testis from the impact of the muscle growth promoting regime. Taken together, this work shows potential long-term harmful effects of strategies aimed at promoting muscle growth by attenuating Activin/Myostatin signalling. Furthermore, we have identified a molecule that could in future be used to overcome the detrimental impact of sActRIIB treatment on the testis.

Published
2021

47. Coordinated activation of both TGFβ and BMP canonical pathways regulates autophagy and tissue regeneration in acetaminophen induced liver injury

Author

Stavropoulos, Athanasios, primary, Divolis, Georgios, additional, Manioudaki, Maria, additional, Gavriil, Ariana, additional, Kloukina, Ismini, additional, Perrea, Despina N., additional, Sountoulidis, Alexandros, additional, Ford, Ethan, additional, Doulou, Athanasia, additional, Apostolidou, Anastasia, additional, Katsantoni, Elena, additional, Ritvos, Olli, additional, Germanidis, Georgios, additional, Xilouri, Maria, additional, and Sideras, Paschalis, additional

Published
2021
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49. Diminution in sperm quantity and quality in mouse models of Duchenne Muscular Dystrophy induced by a myostatin-based muscle growth-promoting intervention

Author

Vaughan, Danielle, Kretz, Oliver, Alqallaf, Ali, Mitchell, Robert, Vaiyapuri, Sakthivel, Matsakas, Antonios, Pasternack, Arja, Collins-Hooper, Henry, Ritvos, Olli, Ballesteros, Randy, Huber, Tobias B., Amthor, Helge, Mukherjee, Abir, and Patel, Ketan

Abstract

Duchenne Muscular Dystrophy is a devastating disease caused by the absence of a functional rod-shaped cytoplasmic protein called dystrophin. Several avenues are being developed aimed to restore dystrophin expression in boys affected by this X-linked disease. However, its complete cure is likely to need combinational approaches which may include regimes aimed at restoring muscle mass. Augmenting muscle growth through the manipulation of the Myostatin/Activin signalling axis has received much attention. However, we have recently shown that while manipulation of this axis in wild type mice using the sActRIIB ligand trap indeed results in muscle growth, it also had a detrimental impact on the testis. Here we examined the impact of administering a powerful Myostatin/Activin antagonist in two mouse models of Duchenne Muscular Dystrophy. We report that whilst the impact on muscle growth was not always positive, both models showed attenuated testis development. Sperm number, motility and ultrastructure were significantly affected by the sActRIIB treatment. Our report suggests that interventions based on Myostatin/Activin should investigate off-target effects on tissues as well as muscle

Published
2020

50. Differentiation of Murine C2C12 Myoblasts Strongly Reduces the Effects of Myostatin on Intracellular Signaling

Author

Lautaoja, Juulia H., Pekkala, Satu, Pasternack, Arja, Laitinen, Mika, Ritvos, Olli, Hulmi, Juha J., Medicum, Department of Physiology, Faculty of Medicine, University of Helsinki, HUS Internal Medicine and Rehabilitation, Department of Medicine, Helsinki University Hospital Area, and Growth factor physiology

Subjects
Muscle Fibers, Skeletal, lcsh:QR1-502, lihakset, lcsh:Microbiology, Article, TGF-BETA SUPERFAMILY, Cell Line, Myoblasts, Mice, tumorkine, Cell Line, Tumor, follistatin, Animals, Humans, CANCER CACHEXIA, skeletal muscle, MUSCLE ATROPHY, lihassolut, Smad, soluviestintä, RECEPTOR, Cell Differentiation, IN-VITRO, Myostatin, musculoskeletal system, MAPK, Activins, LEUKEMIA INHIBITORY FACTOR, ACTIVIN-A, inflammation, Culture Media, Conditioned, CELLS, PROTEIN-SYNTHESIS, myotube, GROWTH, 1182 Biochemistry, cell and molecular biology, proteiinit, 3111 Biomedicine, coculture, Signal Transduction
Abstract

Alongside in vivo models, a simpler and more mechanistic approach is required to study the effects of myostatin on skeletal muscle because myostatin is an important negative regulator of muscle size. In this study, myostatin was administered to murine (C2C12) and human (CHQ) myoblasts and myotubes. Canonical and noncanonical signaling downstream to myostatin, related ligands, and their receptor were analyzed. The effects of tumorkines were analyzed after coculture of C2C12 and colon cancer-C26 cells. The effects of myostatin on canonical and noncanonical signaling were strongly reduced in C2C12 cells after differentiation. This may be explained by increased follistatin, an endogenous blocker of myostatin and altered expression of activin receptor ligands. In contrast, CHQ cells were equally responsive to myostatin, and follistatin remained unaltered. Both myostatin administration and the coculture stimulated pathways associated with inflammation, especially in C2C12 cells. In conclusion, the effects of myostatin on intracellular signaling may be cell line- or organism-specific, and C2C12 myotubes seem to be a nonoptimal in vitro model for investigating the effects of myostatin on canonical and noncanonical signaling in skeletal muscle. This may be due to altered expression of activin receptor ligands and their regulators during muscle cell differentiation.

Published
2020

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