Theme Leader :
Kazuhiro Shigemoto, M.D., Ph.D.
Shuichi Mori, Ph.D., Norio Motohashi, Ph.D.
Adjunct Researcher :
sarcopenia, frailty, muscle atrophy, myasthenia, neuromuscular junction, mesenchymal progenitors, satellite cells, fatty and fibrous degeneration, muscle-specific kinase, metabolic plasticity
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).
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).
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).
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.