雷亚尔1
骨骼肌
细胞生物学
卡尔帕因
化学
信号转导衔接蛋白
兰尼定受体
心肌细胞
肌原纤维
收缩性
磷酸化
胞浆
细胞外
蛋白质降解
生物
内分泌学
生物化学
细胞内
酶
作者
Wei Yan,Minghui Cao,Xianhui Ruan,Li Jiang,Sylvia Lee,Adriana Lemanek,Majid Ghassemian,Donald Pizzo,Yuhao Wan,Yueqing Qiao,Andrew R. Chin,E. Duggan,Dong Wang,John P. Nolan,Jeffrey D. Esko,Simon Schenk,Shizhen Emily Wang
标识
DOI:10.1038/s41556-022-00893-0
摘要
A decline in skeletal muscle mass and low muscular strength are prognostic factors in advanced human cancers. Here we found that breast cancer suppressed O-linked N-acetylglucosamine (O-GlcNAc) protein modification in muscle through extracellular-vesicle-encapsulated miR-122, which targets O-GlcNAc transferase (OGT). Mechanistically, O-GlcNAcylation of ryanodine receptor 1 (RYR1) competed with NEK10-mediated phosphorylation and increased K48-linked ubiquitination and proteasomal degradation; the miR-122-mediated decrease in OGT resulted in increased RYR1 abundance. We further found that muscular protein O-GlcNAcylation was regulated by hypoxia and lactate through HIF1A-dependent OGT promoter activation and was elevated after exercise. Suppressed O-GlcNAcylation in the setting of cancer, through increasing RYR1, led to higher cytosolic Ca2+ and calpain protease activation, which triggered cleavage of desmin filaments and myofibrillar destruction. This was associated with reduced skeletal muscle mass and contractility in tumour-bearing mice. Our findings link O-GlcNAcylation to muscular protein homoeostasis and contractility and reveal a mechanism of cancer-associated muscle dysregulation.
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