ABSTRACT

Glycophagy is the autophagic degradation of glycogen via the lysosomal enzyme GAA/alpha-acid glucosidase. Glycophagy is considered a housekeeping process to degrade poorly branched glycogen particles, but the regulation and role of glycophagy in skeletal muscle metabolism remains enigmatic. Herein, prior muscle contraction promoted glycogen supercompensation 24 and 48 h post contraction, an effect associated with reduced glycophagy. Moreover, NOTCH or cAMP signaling promoted glycophagy, whereas acute glycophagy deficiency rewired cell metabolism by reducing glycolysis and enhancing AMPK and PPAR signaling and fatty acid and glutamine metabolism. These metabolic adaptations were associated with reduced inflammation and triglyceride content but enhanced phosphoinositide 3-kinase (PI3K)-AKT/protein kinase B signaling and insulin action, the latter of which was abolished by exogenous oxidative stress. Collectively, these data suggest glycophagy is dynamically regulated, while the function of glycophagy can be extended beyond a housekeeping process to having an additional role in regulating energy metabolism and insulin action.

Abbreviations: AMPK, AMP-activated protein kinase; ASM, acid soluble metabolites; cAMP, cyclic adenosine monophosphate; EPS, electrical pulse stimulation; FCCP, carbonyl cyanide-p-trifluoromethoxyphenylhydrazone; GAA, glucosidase, alpha, acid; mTOR, mechanistic target of rapamycin kinase; NAD, nicotinamide adenine dinucleotide; PARP, poly (ADP-ribose) polymerase family; PI3K, phosphoinositide 3-kinase; PPAR, peroxisome proliferator activated receptor ; PYGM, muscle glycogen phosphorylase; STBD1, starch binding domain 1; TFEB, transcription factor EB.

摘要

糖化是通过溶酶体酶 GAA/α-酸性葡萄糖苷酶对糖原的自噬降解。糖吞噬被认为是降解分支不良的糖原颗粒的管家过程，但糖吞噬在骨骼肌代谢中的调节和作用仍然是个谜。在此，先前的肌肉收缩促进了收缩后 24 和 48 小时的糖原超补偿，这种效应与减少的糖吞噬有关。此外，NOTCH 或 cAMP 信号促进了糖吞噬，而急性糖吞噬缺乏通过减少糖酵解和增强 AMPK 和 PPAR 信号以及脂肪酸和谷氨酰胺代谢来重新连接细胞代谢。这些代谢适应与减少炎症和甘油三酯含量有关，但增强磷酸肌醇 3-激酶 (PI3K)-AKT/蛋白激酶 B 信号传导和胰岛素作用，后者被外源性氧化应激消除。总的来说，这些数据表明糖吞噬是动态调节的，而糖吞噬的功能可以扩展到管家过程之外，在调节能量代谢和胰岛素作用方面发挥额外作用。

缩写： AMPK，AMP激活的蛋白激酶；ASM，酸溶性代谢物；cAMP，环磷酸腺苷；EPS，电脉冲刺激；FCCP，羰基氰化物-对三氟甲氧基苯腙；GAA，葡萄糖苷酶，α，酸；mTOR，雷帕霉素激酶的机械靶点；NAD，烟酰胺腺嘌呤二核苷酸；PARP，聚（ADP-核糖）聚合酶家族；PI3K，磷酸肌醇 3-激酶；PPAR，过氧化物酶体增殖物激活受体；PYGM，肌糖原磷酸化酶；STBD1，淀粉结合域 1；TFEB，转录因子 EB。