Alternative Titleグルカゴン様ペプチド-1 受容体作動薬であるセマグルチドは，糖尿病合併マウ スにおける慢性肝疾患に起因した骨格筋萎縮を抑制する
Note (General)type:Thesis
A glucagon-like peptide-1 receptor agonist (GLP-1RA) has recently been established as a pharmacological option for the treatment of type 2 diabetes. Recent studies have demonstrated the molecular role of GLP-1R in skeletal muscle homeostasis; however, the therapeutic efficacy of semaglutide, a GLP-1RA, on skeletal muscle atrophy in chronic liver disease (CLD) under diabetic conditions remains unclear. In the present study, semaglutide effectively inhibited psoas muscle atrophy and suppressed declines in grip strength in a diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet-fed diabetic KK-Ay mouse model. Moreover, semaglutide inhibited ubiquitin-proteosome-mediated skeletal muscle proteolysis and promoted myogenesis in palmitic acid (PA)-stimulated C2C12 murine myocytes. Mechanistically, this effect of semaglutide on skeletal muscle atrophy was mediated by multiple functional pathways. First, semaglutide protected against hepatic injury in mice accompanied by increased production of insulin-like growth factor 1 and reduced accumulation of reactive oxygen species (ROS). These effects were associated with decreased proinflammatory cytokines and ROS accumulation, leading to the suppression of ubiquitin-proteosome muscle degradation. Moreover, semaglutide inhibited the amino acid starvation-related stress signaling that was activated under chronic liver injury, resulting in the recovery of the mammalian target of rapamycin activity in the skeletal muscle of DDC-diet fed KK-Ay mice. Second, semaglutide improved skeletal muscle atrophy by directly stimulating GLP-1R in myocytes. Semaglutide induced cAMP-mediated activation of PKA and AKT, enhanced mitochondrial biogenesis, and reduced ROS accumulation, thereby resulting in inhibition of NF-κB/myostatin-mediated ubiquitin-proteosome degradation and the augmentation of heat-shock factor-1-mediated myogenesis. Collectively, semaglutide may have potential as a new therapeutic strategy for CLD-related skeletal muscle wasting.
権利情報：© 2023 Elsevier B.V. All rights reserved.
identifier:Biochimica et Biophysica Acta-Molecular Basis of Disease. 2023 Oct, vol.1869, no.7, article no.166770
identifier:0925-4439
identifier:http://ginmu.naramed-u.ac.jp/dspace/handle/10564/4362
identifier:Biochimica et Biophysica Acta-Molecular Basis of Disease, 1869(7): 166770
Collection (particular)国立国会図書館デジタルコレクション > デジタル化資料 > 博士論文
Date Accepted (W3CDTF)2024-09-06T22:07:41+09:00
Data Provider (Database)国立国会図書館 : 国立国会図書館デジタルコレクション