Future perspectives

I have provided compelling evidence that IL-1α/β is involved in proper regeneration, especially at early phase of the regeneration process, in damaged muscle tissues. The pro-regenerative effect of IL-1s is likely to be achieved, not only via amplification of immune responses to the site of injury, but also via the intrinsic capabilities of myoblasts. Further clarification of the roles and the mechanisms underlying the actions of IL-1s should provide insights that will enhance the understanding of the important interactions between inflammatory environments and satellite cell regulation within regenerating skeletal muscles.

The current thesis did not investigate the other types of muscle injury, while the most common form of injury occurred in muscle tissues is mechanical stress. It is conceivable to obtain the knowledge from this model and further explore the immune response and tissue remodeling in exercised muscles, that outcrossed from mechanical and biochemical injuries. Interestingly, recent documents showed the IL-1 released locally in exercised muscle also exerts the beneficial role in metabolic regulations via glucose homeostasis(Tsuchiya et al.,

2018). These imply the IL-1 as a functional molecule that could be another target for maintenance of both muscle structure and performance.

In a clinical perspective, understanding of the immune system that have a close relationship to the muscle regeneration could benefit either the development of effective treatment for muscle disorders, or even give cautions in current therapeutic strategies that may affect muscle functions. For example, the manipulation of systemic inflammatory responses from pharmacological blocking could resulted in the altered muscle regenerative capacity (Mackey et al., 2007; Teixeira et al., 2003). And finally, a well-maintenance of skeletal muscle tissue is important not only for physical independence, but also offers the defense for metabolic morbidities and contributes to the health longevity.

List of scientific publications and presentations The dissertation is based on the following works:

- Chaweewannakorn C, Tsuchiya M, Koide M, Hatakeyama H, Tanaka Y, Yoshida S, Sugawara S, Hagiwara Y, Sasaki K, Kanzaki M, Roles of IL-1α/β in regeneration of cardiotoxin-injured muscle and satellite cell function. Am J Physiol Regul Integr Comp Physiol, Issue 1, Volume 315, R90-R103, July 2018.

- Chaweewannakorn C, Tsuchiya M, Koide M, Hagiwara Y, Kanzaki M, Hatakeyama H, Sasaki K, Involvement of interleukin-1 cytokine networks in skeletal muscle myogenesis (Poster presentation), Japan Muscle Society Annual Meeting 2016, August 5-6, 2016

- Chaweewannakorn C, Tsuchiya M, Kanzaki M, Hagiwara Y, Hatakeyama H, Koide M, Yoshida S, Sasaki K, Roles of Interleukin-1 in mediating the skeletal muscle activity (Poster presentation), The Asian Academy of Craniomandibular Disorders (AACMD) Congress, Jakarta, Indonesia, October 21-22, 2017

- Chaweewannakorn C, Hatakeyama H, Tsuchiya M, Hagiwara Y, Koide M, Yoshida S, Kanzaki M, Sasaki K, Interleukin-1β modulates in-vitro myoblast fusion via enhancing the actin cytoskeleton activity (Poster presentation), The American Society of Cell Biology (ASCB) Annual Meeting, Philadelphia, PA, USA, December 2-6, 2017

Publications by the author do not included in this dissertation:

- Tsuchiya M, Sekiai S, Hatakeyama H, Koide M, Chaweewannakorn C, Yaoita F, Tan-No K, Sasaki K, Watanabe M, Sugawara S, Endo Y, Itoi E, Hagiwara Y, Kanzaki M, Neutrophils provide a favorable IL-1-mediated immunometabolic niche that primes GLUT4 translocation and performance in working skeletal muscles. Cell Reports, Issue 8, Volume 23, P2354-2364, May 2018.

- Yoshida S, Hagiwara Y, Tsuchiya M, Shinoda M, Koide M, Hatakeyama H, Chaweewannakorn C, Yano T, Sogi Y, Itaya N, Sekiguchi T, Yabe Y, Sasaki K, Kanzaki M, Itoi E, Involvement of neutrophils and interleukin-18 in nociception in a mouse model of muscle pain, Mol Pain, Volume 14, February 2018

- Chaweewannakorn C, Sekiai S, Tsuchiya M, Koide M, Hatakeyama H, Sasaki K, Hagiwara Y, Kanzaki M, Roles of IL-1β and neutrophils in GLUT4 translocation and muscle performance during exercise (Poster presentation), FASEB Science Research Conference, Snowmass, CO, USA, July 16-21, 2017 - Chaweewannakorn C, IL-1 provided from neutrophils supports the masticatory activity with the enhancing muscle satellite cell proliferation and function (Oral presentation), 先端⻭歯学スクール2018, Tokyo, Japan, August 23-24, 2018

Acknowledgements

This thesis was conducted in collaboration between Tohoku University Graduate School of Dentistry, Graduate School of Biomedical Engineering and Graduate School of Medicine. During four years of my doctoral course, I sincerely appreciated lots of help and advice through the completion of research.

First of all, I would like to express gratitude to my chief advisor, Professor Keiichi Sasaki, for supporting me with a great opportunity to pursue the doctoral degree in Tohoku University. I am deeply grateful for all my advisors, Associate Professor Makoto Kanzaki and Associate Professor Masahiro Tsuchiya for their valuable advice and encouragement throughout the study. Thank you for teaching me all about basic science research and scientific writing with all your patience and kindness, and also for creating such an inspiring work environment with great colleagues. And I must appreciate Professor Yoshihiro Hagiwara and all co-author doctors from Department of orthopaedic surgery, Graduate School of Medicine.

Next I would like to express my sincere and appreciation to the examination committee, who have accepted to evaluate my work and provided the valuable criticism questions and suggestion to improve the dissertation.

I spent most years in Kanzaki Laboratory of the Graduate School of Biomedical Engineering, where I learnt and practiced all my experiments, and also improved my Japanese. Here I thanks Dr.Hiroyasu Hatakeyama who helped me a lot with his expertise in microscopy and imaging. I also thank our technical assistants, Mrs.Natsumi Emoto and Mrs.Fumie Wagatsuma for their technical help and for keeping the lab in order throughout these years. And I would like to thank all the members in Kanzaki laboratory and Division of Advanced Prosthetic Dentistry for their kind and welcome.

Lastly, thanks to my family and colleagues in Chulalongkorn university for their big support through these years as always.

References

Alexsandra da Silva Neto Trajano, L., da Silva, C. L., de Carvalho, S. N., Cortez, E., Mencalha, A. L., de Souza da Fonseca, A., & Stumbo, A. C. (2016).

Cell viability, reactive oxygen species, apoptosis, and necrosis in myoblast cultures exposed to low-level infrared laser. Lasers Med Sci, 31(5), 841-848. doi:10.1007/s10103-016-1909-8

Arnold, L., Henry, A., Poron, F., Baba-Amer, Y., van Rooijen, N., Plonquet, A., Chazaud, B. (2007). Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis. J Exp Med, 204(5), 1057-1069.

Authier, F. J., Chazaud, B., Plonquet, A., Eliezer-Vanerot, M. C., Poron, F., Belec, L., Gherardi, R. K. (1999). Differential expression of the IL-1 system components during in vitro myogenesis: implication of IL-1beta in induction of myogenic cell apoptosis. Cell Death Differ, 6(10), 1012-1021.

doi:10.1038/sj.cdd.4400576

Baeza-Raja, B., & Munoz-Canoves, P. (2004). p38 MAPK-induced nuclear factor-kappaB activity is required for skeletal muscle differentiation: role of interleukin-6. Mol Biol Cell, 15(4), 2013-2026.

Broussard, S. R., McCusker, R. H., Novakofski, J. E., Strle, K., Shen, W. H., Johnson, R. W., Kelley, K. W. (2004). IL-1beta impairs insulin-like growth factor i-induced differentiation and downstream activation signals of the insulin-like growth factor i receptor in myoblasts. J Immunol, 172(12), 7713-7720.

Carvajal Monroy, P. L., Grefte, S., Kuijpers-Jagtman, A. M., Von den Hoff, J.

W., & Wagener, F. A. (2017). Neonatal Satellite Cells Form Small Myotubes In Vitro. J Dent Res, 96(3), 331-338.

doi:10.1177/0022034516679136

Charge, S. B., & Rudnicki, M. A. (2004). Cellular and molecular regulation of muscle regeneration. Physiol Rev, 84(1), 209-238.

doi:10.1152/physrev.00019.2003

Charrasse, S., Causeret, M., Comunale, F., Bonet-Kerrache, A., & Gauthier-Rouviere, C. (2003). Rho GTPases and cadherin-based cell adhesion in skeletal muscle development. J Muscle Res Cell Motil, 24(4-6), 309-313.

Chiba, K., Tsuchiya, M., Koide, M., Hagiwara, Y., Sasaki, K., Hattori, Y., Endo, Y. (2015). Involvement of IL-1 in the Maintenance of Masseter Muscle Activity and Glucose Homeostasis. PLoS One, 10(11), e0143635.

doi:10.1371/journal.pone.0143635

Collins, R. A., & Grounds, M. D. (2001). The role of tumor necrosis factor-alpha (TNF-alpha) in skeletal muscle regeneration. Studies in TNF-alpha(-/-) and TNF-alpha(-/-)/LT-alpha(-/-) mice. J Histochem Cytochem, 49(8), 989-1001. doi:10.1177/002215540104900807

Costamagna, D., Costelli, P., Sampaolesi, M., & Penna, F. (2015). Role of Inflammation in Muscle Homeostasis and Myogenesis. Mediators Inflamm, 2015, 805172. doi:10.1155/2015/805172

Deasy, B. M., Lu, A., Tebbets, J. C., Feduska, J. M., Schugar, R. C., Pollett, J. B., Huard, J. (2007). A role for cell sex in stem cell-mediated skeletal muscle regeneration: female cells have higher muscle regeneration efficiency. J Cell Biol, 177(1), 73-86.

Di Paolo, N. C., & Shayakhmetov, D. M. (2016). Interleukin 1alpha and the inflammatory process. Nat Immunol, 17(8), 906-913.

Forrester, J. S., & Bick-Forrester, J. (2005). Persistence of inflammatory cytokines cause a spectrum of chronic progressive diseases: implications for therapy. Med Hypotheses, 65(2), 227-231.

doi:10.1016/j.mehy.2005.03.010

Fry, C. S., Kirby, T. J., Kosmac, K., McCarthy, J. J., & Peterson, C. A. (2017).

Myogenic Progenitor Cells Control Extracellular Matrix Production by Fibroblasts during Skeletal Muscle Hypertrophy. Cell Stem Cell, 20(1), 56-69. doi:10.1016/j.stem.2016.09.010

Garry, G. A., Antony, M. L., & Garry, D. J. (2016). Cardiotoxin Induced Injury and Skeletal Muscle Regeneration. Methods Mol Biol, 1460, 61-71.

doi:10.1007/978-1-4939-3810-0_6

Grabiec, K., Tokarska, J., Milewska, M., Blaszczyk, M., Gajewska, M., &

Grzelkowska-Kowalczyk, K. (2013). Interleukin-1beta stimulates early myogenesis of mouse C2C12 myoblasts: the impact on myogenic regulatory factors, extracellular matrix components, IGF binding proteins and protein kinases. Pol J Vet Sci, 16(2), 255-264.

Griffin, C. A., Apponi, L. H., Long, K. K., & Pavlath, G. K. (2010). Chemokine expression and control of muscle cell migration during myogenesis. J Cell Sci, 123(Pt 18), 3052-3060.

Gruenbaum-Cohen, Y., Harel, I., Umansky, K. B., Tzahor, E., Snapper, S. B., Shilo, B. Z., & Schejter, E. D. (2012). The actin regulator N-WASp is required for muscle-cell fusion in mice. Proc Natl Acad Sci U S A, 109(28), 11211-11216.

Hardy, D., Besnard, A., Latil, M., Jouvion, G., Briand, D., Thepenier, C., . . . Chretien, F. (2016). Comparative Study of Injury Models for Studying Muscle Regeneration in Mice. PLoS One, 11(1), e0147198.

doi:10.1371/journal.pone.0147198

Hatakeyama, H., Nakahata, Y., Yarimizu, H., & Kanzaki, M. (2017). Live-cell single-molecule labeling and analysis of myosin motors with quantum dots.

Mol Biol Cell, 28(1), 173-181.

Heredia, J. E., Mukundan, L., Chen, F. M., Mueller, A. A., Deo, R. C., Locksley, R. M., Chawla, A. (2013). Type 2 innate signals stimulate fibro/adipogenic progenitors to facilitate muscle regeneration. Cell, 153(2), 376-388.

Holmes, David. (2017). Physiologic role of IL-1β in glucose homeostasis. Nature Reviews Endocrinology, 13, 128. doi:10.1038/nrendo.2017.11

Horai, R., Asano, M., Sudo, K., Kanuka, H., Suzuki, M., Nishihara, M., Iwakura, Y. (1998). Production of mice deficient in genes for interleukin (IL)-1alpha, IL-1beta, IL-1alpha/beta, and IL-1 receptor antagonist shows that IL-1beta is crucial in turpentine-induced fever development and glucocorticoid secretion. J Exp Med, 187(9), 1463-1475.

Joseph, G. A., Lu, M., Radu, M., Lee, J. K., Burden, S. J., Chernoff, J., & Krauss, R. S. (2017). Group I Paks Promote Skeletal Myoblast Differentiation In Vivo and In Vitro. Mol Cell Biol, 37(4).

Karalaki, M., Fili, S., Philippou, A., & Koutsilieris, M. (2009). Muscle regeneration: cellular and molecular events. In Vivo, 23(5), 779-796.

Klein, S. L., & Flanagan, K. L. (2016). Sex differences in immune responses. Nat Rev Immunol, 16(10), 626-638. doi:10.1038/nri.2016.90

Kohno, S., Yamashita, Y., Abe, T., Hirasaka, K., Oarada, M., Ohno, A., Nikawa, T. (2012). Unloading stress disturbs muscle regeneration through perturbed recruitment and function of macrophages. J Appl Physiol (1985), 112(10), 1773-1782.

Lee, J. G., & Heur, M. (2014). Interleukin-1beta-induced Wnt5a enhances human corneal endothelial cell migration through regulation of Cdc42 and RhoA.

Mol Cell Biol, 34(18), 3535-3545.

Liu, N., Garry, G. A., Li, S., Bezprozvannaya, S., Sanchez-Ortiz, E., Chen, B., Olson, E. N. (2017). A Twist2-dependent progenitor cell contributes to adult skeletal muscle. Nat Cell Biol, 19(3), 202-213.

Mackey, A. L., Kjaer, M., Dandanell, S., Mikkelsen, K. H., Holm, L., Dossing, S., Langberg, H. (2007). The influence of anti-inflammatory medication

on exercise-induced myogenic precursor cell responses in humans. J Appl Physiol (1985), 103(2), 425-431. doi:10.1152/japplphysiol.00157.2007 Mackiewicz, Z., Hukkanen, M., Povilenaite, D., Sukura, A., Fonseca, J. E.,

Virtanen, I., & Konttinen, Y. T. (2003). Dual effects of caspase-1, interleukin-1 beta, tumour necrosis factor-alpha and nerve growth factor receptor in inflammatory myopathies. Clin Exp Rheumatol, 21(1), 41-48.

Mahdy, Mohamed A. A., Lei, Hsiao Yin, Wakamatsu, Jun-Ichi, Hosaka, Yoshinao Z., & Nishimura, Takanori. (2015). Comparative study of muscle regeneration following cardiotoxin and glycerol injury. Annals of Anatomy - Anatomischer Anzeiger, 202, 18-27.

doi:https://doi.org/10.1016/j.aanat.2015.07.002

Mauro, A. (1961). Satellite cell of skeletal muscle fibers. J Biophys Biochem Cytol, 9, 493-495.

Mayadas, Tanya N., Cullere, Xavier, & Lowell, Clifford A. (2014). The multifaceted functions of neutrophils. Annual review of pathology, 9, 181-218. doi:10.1146/annurev-pathol-020712-164023

Millay, D. P., O'Rourke, J. R., Sutherland, L. B., Bezprozvannaya, S., Shelton, J.

M., Bassel-Duby, R., & Olson, E. N. (2013). Myomaker is a membrane activator of myoblast fusion and muscle formation. Nature, 499(7458), 301-305.

Mueck, T., Berger, F., Buechsler, I., Valchanova, R. S., Landuzzi, L., Lollini, P.

L., Munz, B. (2011). TRAF6 regulates proliferation and differentiation of skeletal myoblasts. Differentiation, 81(2), 99-106.

doi:10.1016/j.diff.2010.11.002

Munoz-Canoves, P., Scheele, C., Pedersen, B. K., & Serrano, A. L. (2013).

Interleukin-6 myokine signaling in skeletal muscle: a double-edged sword?

FEBS J, 280(17), 4131-4148.

Nedachi, T., Hatakeyama, H., Kono, T., Sato, M., & Kanzaki, M. (2009).

Characterization of contraction-inducible CXC chemokines and their roles in C2C12 myocytes. Am J Physiol Endocrinol Metab, 297(4), E866-878.

doi:10.1152/ajpendo.00104.2009

Oliveira Cde, F., Lopes Dda, S., Mendes, M. M., Homsi-Brandeburgo, M. I., Hamaguchi, A., de Alcantara, T. M., Rodrigues Vde, M. (2009). Insights of local tissue damage and regeneration induced by BnSP-7, a myotoxin isolated from Bothrops (neuwiedi) pauloensis snake venom. Toxicon, 53(5), 560-569. doi:10.1016/j.toxicon.2008.12.025

Ono, Y., Boldrin, L., Knopp, P., Morgan, J. E., & Zammit, P. S. (2010). Muscle satellite cells are a functionally heterogeneous population in both somite-derived and branchiomeric muscles. Dev Biol, 337(1), 29-41.

doi:10.1016/j.ydbio.2009.10.005

Osses, N., & Brandan, E. (2002). ECM is required for skeletal muscle differentiation independently of muscle regulatory factor expression. Am J Physiol Cell Physiol, 282(2), C383-394. doi:10.1152/ajpcell.00322.2001 Otis, J. S., Niccoli, S., Hawdon, N., Sarvas, J. L., Frye, M. A., Chicco, A. J., &

Lees, S. J. (2014). Pro-inflammatory mediation of myoblast proliferation.

PLoS One, 9(3), e92363.

Rider, P., Carmi, Y., Guttman, O., Braiman, A., Cohen, I., Voronov, E., Apte, R.

N. (2011). IL-1alpha and IL-1beta recruit different myeloid cells and promote different stages of sterile inflammation. J Immunol, 187(9), 4835-4843. doi:10.4049/jimmunol.1102048

Rosales, Carlos. (2018). Neutrophil: A Cell with Many Roles in Inflammation or Several Cell Types? Frontiers in physiology, 9, 113-113.

doi:10.3389/fphys.2018.00113

Ruffell, D., Mourkioti, F., Gambardella, A., Kirstetter, P., Lopez, R. G., Rosenthal, N., & Nerlov, C. (2009). A CREB-C/EBPbeta cascade induces M2 macrophage-specific gene expression and promotes muscle injury repair. Proc Natl Acad Sci U S A, 106(41), 17475-17480.

Sachidanandan, C., Sambasivan, R., & Dhawan, J. (2002). Tristetraprolin and LPS-inducible CXC chemokine are rapidly induced in presumptive satellite cells in response to skeletal muscle injury. J Cell Sci, 115(Pt 13), 2701-2712.

Sahni, A., Guo, M., Sahni, S. K., & Francis, C. W. (2004). Interleukin-1beta but not IL-1alpha binds to fibrinogen and fibrin and has enhanced activity in the bound form. Blood, 104(2), 409-414. doi:10.1182/blood-2004-01-0126 Serrano, A. L., Baeza-Raja, B., Perdiguero, E., Jardi, M., & Munoz-Canoves, P.

(2008). Interleukin-6 is an essential regulator of satellite cell-mediated skeletal muscle hypertrophy. Cell Metab, 7(1), 33-44.

doi:10.1016/j.cmet.2007.11.011

Sims, John E., & Smith, Dirk E. (2010). The IL-1 family: regulators of immunity.

Nature Reviews Immunology, 10, 89. doi:10.1038/nri2691 https://www.nature.com/articles/nri2691 - supplementary-information

Strle, K., Broussard, S. R., McCusker, R. H., Shen, W. H., Johnson, R. W., Freund, G. G., Kelley, K. W. (2004). Proinflammatory cytokine impairment of

insulin-like growth factor I-induced protein synthesis in skeletal muscle myoblasts requires ceramide. Endocrinology, 145(10), 4592-4602.

doi:10.1210/en.2003-1749

Tedesco, F. S., Dellavalle, A., Diaz-Manera, J., Messina, G., & Cossu, G. (2010).

Repairing skeletal muscle: regenerative potential of skeletal muscle stem cells. J Clin Invest, 120(1), 11-19.

Tedesco, Francesco Saverio, Dellavalle, Arianna, Diaz-Manera, Jordi, Messina, Graziella, & Cossu, Giulio. (2010). Repairing skeletal muscle:

regenerative potential of skeletal muscle stem cells. The Journal of clinical investigation, 120(1), 11-19. doi:10.1172/JCI40373

Teixeira, C. F., Zamuner, S. R., Zuliani, J. P., Fernandes, C. M., Cruz-Hofling, M. A., Fernandes, I., Gutierrez, J. M. (2003). Neutrophils do not contribute to local tissue damage, but play a key role in skeletal muscle regeneration, in mice injected with Bothrops asper snake venom. Muscle Nerve, 28(4), 449-459. doi:10.1002/mus.10453

Teng, S., Stegner, D., Chen, Q., Hongu, T., Hasegawa, H., Chen, L., Huang, P.

(2015). Phospholipase D1 facilitates second-phase myoblast fusion and skeletal muscle regeneration. Mol Biol Cell, 26(3), 506-517.

Tidball, J. G., & Villalta, S. A. (2010). Regulatory interactions between muscle and the immune system during muscle regeneration. Am J Physiol Regul Integr Comp Physiol, 298(5), R1173-1187.

Tierney, M. T., Aydogdu, T., Sala, D., Malecova, B., Gatto, S., Puri, P. L., Sacco, A. (2014). STAT3 signaling controls satellite cell expansion and skeletal muscle repair. Nat Med, 20(10), 1182-1186.

Tsuchiya, Masahiro, Sekiai, Shigenori, Hatakeyama, Hiroyasu, Koide, Masashi, Chaweewannakorn, Chayanit, Yaoita, Fukie, Kanzaki, Makoto. (2018).

Neutrophils Provide a Favorable IL-1-Mediated Immunometabolic Niche that Primes GLUT4 Translocation and Performance in Skeletal Muscles.

Cell Reports, 23(8), 2354-2364. doi:10.1016/j.celrep.2018.04.067

Vasyutina, E., Martarelli, B., Brakebusch, C., Wende, H., & Birchmeier, C.

(2009). The small G-proteins Rac1 and Cdc42 are essential for myoblast fusion in the mouse. Proc Natl Acad Sci U S A, 106(22), 8935-8940.

Voss, J. G., Shagal, A. G., Tsuji, J. M., MacDonald, J. W., Bammler, T. K., Farin, F. M., & St Pierre Schneider, B. (2017). Time Course of Inflammatory Gene Expression Following Crush Injury in Murine Skeletal Muscle. Nurs Res, 66(2), 63-74. doi:10.1097/nnr.0000000000000209