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.

骨骼肌质量下降和肌肉力量低下是晚期人类癌症的预后因素。在这里，我们发现乳腺癌通过细胞外囊泡封装的 miR-122 抑制肌肉中的O连接N -乙酰氨基葡萄糖 ( O -GlcNAc) 蛋白修饰，miR-122 靶向O -GlcNAc 转移酶 (OGT)。从机制上讲，兰尼碱受体 1 (RYR1) 的O -GlcNAc 酰化与 NEK10 介导的磷酸化竞争，并增加 K48 相关的泛素化和蛋白酶体降解。miR-122介导的OGT减少导致RYR1丰度增加。我们进一步发现，肌肉蛋白O -GlcNAcNA 酰化通过 HIF1A 依赖性 OGT 启动子激活受到缺氧和乳酸的调节，并在运动后升高。在癌症环境中，通过增加 RYR1抑制O -GlcNAc 基化，导致胞质 Ca ²⁺和钙蛋白酶激活更高，从而引发结蛋白丝的裂解和肌原纤维的破坏。这与荷瘤小鼠骨骼肌质量和收缩力的减少有关。我们的研究结果将O -GlcNAc 酰化与肌肉蛋白稳态和收缩性联系起来，并揭示了癌症相关肌肉失调的机制。