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Gerontology of motor system


Theme Leader :
Kazuhiro Shigemoto, M.D., Ph.D.
Researcher :
Shuichi Mori, Ph.D., Norio Motohashi, Ph.D.
Adjunct Researcher :
Natsumi Ooishi


sarcopenia, frailty, muscle atrophy, myasthenia, neuromuscular junction, mesenchymal progenitors, satellite cells, fatty and fibrous degeneration, muscle-specific kinase, metabolic plasticity

Major Research Titles

  1. Muscle atrophy
    1. ( 1 ) Maintenance of neuromuscular system by the interactions between muscle and motor neuron.
    2. ( 2 ) Molecular mechanisms of muscle atrophy.
    3. ( 3 ) New strategies for prevention, therapies and diagnosis of muscle atrophy.


A critical issue in today's aging society is the need to reduce the burden of family care while continuing to improve our medical institutions. A rapidly emerging, major health concern is sarcopenia, the debilitating effect of muscle weakness and atrophy from aging. Our research aim is to elucidate the molecular mechanisms of muscle atrophy and generate new therapies for reducing disability by aging.
Currently, the practical clinical definition and consensus diagnostic criteria for age-related sarcopenia are based on muscle mass, strength and physical performance (Figure 1).

Figure 1

However, the molecular basis of sarcopenia condition is still not well understood. It is caused by gradual changes in multiple factors, involving both physical and environmental conditions over the life span. Determining and focusing on the most critical issues is necessary to elucidate the molecular mechanisms of age-related muscle atrophy. We believe it is important to understand how the motor system of muscles and motoneurons is maintained by mutual interactions through neuromuscular junctions (NMJs) (Figure 2).

Figure 2

Rapid loss of skeletal muscle protein results from imbalance in the rate of muscle protein synthesis and degradation after functional or physical denervation. The progression of partial denervation with age increases skeletal muscle loss and reduces functions each year (Figure 3).

Figure 3

Furthermore, the failure of muscle functions may diminish retrograde signals, which preserve the functions and structures of NMJs.
In 2006, we demonstrated that muscle-specific kinase (MuSK) is required for the maintenance of NMJs and that autoantibodies against MuSK cause myasthenia gravis (MG), using animalmodels of MuSK MG. MuSK is expressed at the postsynaptic membrane of NMJs and is essential for their formation. MuSK and downstream signaling are required for a complex exchange of signals between motor neurons and muscle fibers that leads to the maintenance of a highly specialized postsynaptic membrane and a differentiated nerve terminal. The disruption of these dynamic interactions by MuSK antibodies causes MG with muscle weakness and atrophy. In 2012, we established a new mouse model of MuSK MG , clarified the pathogenesis of human disease and paved the way for the development of new therapies for the disease (->The Jackson Laboratory web site). The disease models are useful not only for studying the pathogenesis and treatment of MuSK MG, but also for understanding the molecular mechanisms of neuromuscular maintenance.


  1. 1. Mori S., Motohashi N., Takashima R., Kishi M., Nishimune H. and Shigemoto K. Immunization of mice with LRP4 induces myasthenia similar to MuSK-associated myasthenia gravis. Exp Neurol 297: 158-167, 2017.
  2. 2. Nishimune H., Badddawi Y., Mori S. and Shigemoto K. Dual-color STED microscopy reveals a sandwich structure of Bassoon and Piccolo in active zones of adult and aged mice. Scientific Reports 6: 27935 (e1-e12), 2016.
  3. 3. Shigemoto K., Motohashi N. and Mori S. Metabolic plasticity in sarcopenia. J Phys Fitness Sports Med 4: 347-350, 2015.
  4. 4. Phillips WE., Christadoss P., Losen M., Punga A., Shigemoto K., Vershuuren J. and Vincent A. (Guidelines for preclinical animal and cellular models of MuSK-myasthenia gravis.) Exp Neurol: 270, 29-40, 2015.
  5. 5. Mori, S., and Shigemoto, K. Mechanisms associated with the pathogenicity of antibodies against muscle-specific kinase in myasthenia gravis. Autoimmun Rev 12: 912-917, 2013.
  6. 6. Mori, S., Kubo, S., Akiyoshi, T., Yamada, S., Miyazaki, T., Hotta, H., Desaki, J., Kishi, M., Konishi, T., Nishino, Y., Miyazawa, A., Maruyama, N., and Shigemoto, K. Antibodies against muscle-specific kinase impair both presynaptic and postsynaptic functions in a murine model of myasthenia gravis. The American Journal of Pathology 180: 798-810, 2012.
  7. 7. Mori, S., Kishi, M., Kubo, S., Akiyoshi, T., Yamada, S., Miyazaki, T., Konishi, T., Maruyama, N., and Shigemoto, K. 3,4-Diaminopyridine improves neuromuscular transmission in a MuSK antibody-induced mouse model of myasthenia gravis. Journal of Neuroimmunology 245: 75-78, 2012.
  8. 8. Mori, S., Yamada, S., Kubo, S., Chen, J., Matsuda, S., Shudou, M., Maruyama, N., and Shigemoto, K. Divalent and monovalent autoantibodies cause dysfunction of MuSK by distinct mechanisms in a rabbit model of myasthenia gravis. Journal of Neuroimmunology 244: 1-7, 2012.
  9. 9. Shigemoto, K., Kubo, S., Mori, S., Yamada, S., Akiyoshi, T., and Miyazaki, T. Muscle weakness and neuromuscular junctions in aging and disease. Geriatr Gerontol Int 10 Suppl 1:S137-147, 2010.
  10. 10. Shigemoto, K., Kubo, S., Jie, C., Hato, N., Abe, Y., Ueda, N., Kobayashi, N., Kameda, K., Mominoki, K., Miyazawa, A., et al. Myasthenia gravis experimentally induced with muscle-specific kinase. Ann N Y Acad Sci 1132: 93-98, 2008.
  11. 11. Konishi, T., Ohta, K., Shigemoto, K., and Ohta, M. Anti-alkaline phosphatase antibody positive myasthenia gravis. J Neurol Sci 263:89-93, 2007
  12. 12. Ohta, K., Shigemoto, K., Fujinami, A., Maruyama, N., Konishi, T., and Ohta, M. Clinical and experimental features of MuSK antibody positive MG in Japan. Eur J Neurol 14:1029-1034, 2007.
  13. 13. Shigemoto, K., Kubo, S., Maruyama, N., Hato, N., Yamada, H., Jie, C., Kobayashi, N., Mominoki, K., Abe, Y., Ueda, N., et al. Induction of myasthenia by immunization against muscle-specific kinase. J Clin Invest 116:1016-1024, 2006
  14. 14. Ohta, K., Shigemoto, K., Kubo, S., Maruyama, N., Abe, Y., Ueda, N., Fujinami, A., and Ohta, M. MuSK Ab described in seropositive MG sera found to be Ab to alkaline phosphatase. Neurology 65:1988, 2005.
  15. 15. Manktelow, E., Shigemoto, K., and Brierley, I. Characterization of the frameshift signal of Edr, a mammalian example of programmed -1 ribosomal frameshifting. Nucleic Acids Res 33:1553-1563, 2005.
  16. 16. Ohta, K., Shigemoto, K., Kubo, S., Maruyama, N., Abe, Y., Ueda, N., and Ohta, M. MuSK antibodies in AChR Ab-seropositive MG vs AChR Ab-seronegative MG. Neurology 62:2132-2133, 2004.
  17. 17. Shigemoto, K., Brennan, J., Walls, E., Watson, C.J., Stott, D., Rigby, P.W., and Reith, A.D. 2001. Identification and characterisation of a developmentally regulated mammalian gene that utilises -1 programmed ribosomal frameshifting. Nucleic Acids Res 29:4079-4088.
  18. 18. Shigemoto, K., Kubo, S., Maruyama, N., Yamada, S., Obata, K., Kikuchi, K., and Kondo, I. Identification and characterization of 5' extension of mammalian agrin cDNA, the exons and the promoter sequences. Biochim Biophys Acta 1494:170-174, 2000.