Research projects

Although patients with skeletal muscle atrophy exhibit a poorer prognosis in sepsis, the underlying mechanisms remain largely undefined. To investigate this relationship, the applicant established a murine model of skeletal muscle atrophy induced by sciatic nerve transection (DN) and examined its impact on sepsis progression. The results demonstrated that DN mice exhibited aggravated sepsis, accompanied by an increased proportion of splenic T cells expressing the immune checkpoint molecule cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Furthermore, when exosomes isolated from the atrophied skeletal muscle of septic DN mice were applied to splenocytes from healthy mice, there was a notable increase in CTLA-4+CD4+ T cells. These findings suggest that exacerbation of sepsis in the context of skeletal muscle atrophy may be mediated by excessive activation of immunosuppressive pathways driven by exosomes derived from atrophied skeletal muscle.

申請者は萎縮した骨格筋が腎臓の線維化を抑制するという興味深い現象を確認した。この機序の全貌は全く未解明であるが、申請者は骨格筋萎縮下で産出されたマウス血清中の脂質二重膜構造を有する細胞外小胞が強力な抗線維化作用を有している可能性を見出し、その細胞外小胞が新規抗線維化治療薬としてのモダリティとして優れているのではないかと考えた。そこで坐骨神経切断による廃用性筋萎縮モデルマウス血清由来細胞外小胞のブレオマイシン誘発肺線維症モデルおよび四塩化炭素誘発肝線維化モデルに対しする抗線維化効果について検討する。

In a mouse model of chronic kidney disease (CKD), the skeletal muscle weight and the cross-sectional area of the muscle fiber appeared to gradually decrease after the CKD surgery; expression of apelin-a skeletal muscle-derived secretory factor also decreased in the skeletal muscles. The administration of charcoal, a uremic toxin adsorbent, suppressed the decrease in apelin and skeletal muscle mass. Furthermore, apelin suppressed the decrease in skeletal muscle mass in CKD mice. The findings suggest that uremic toxin-mediated downregulation of apelin may play an important role in the pathophysiology of CKD-induced sarcopenia. Apelin, therefore could be a promising therapeutic target for CKD-induced sarcopenia.