Regulation and role of glycophagy in skeletal muscle energy metabolism

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. <b>Abbreviations:</b> 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.

糖原自噬（Glycophagy）是通过溶酶体酶GAA/α-酸性葡糖苷酶实现糖原的自噬降解。糖原自噬曾被认为是降解分支异常糖原颗粒的持家过程，但其在骨骼肌代谢中的调控机制与功能仍尚不明确。本研究中，肌肉收缩预处理可在收缩后24小时与48小时促进糖原超补偿，该效应与糖原自噬水平降低相关。此外，Notch与环腺苷酸单磷酸（cyclic adenosine monophosphate, cAMP）信号通路可促进糖原自噬；而急性糖原自噬缺陷则通过抑制糖酵解、激活AMP活化蛋白激酶（AMP-activated protein kinase, AMPK）与过氧化物酶体增殖物激活受体（peroxisome proliferator activated receptor, PPAR）信号通路，以及增强脂肪酸与谷氨酰胺代谢，重塑细胞代谢网络。上述代谢适应性改变与炎症水平降低、甘油三酯含量减少相关，同时可增强磷脂酰肌醇3-激酶（phosphoinositide 3-kinase, PI3K）-AKT/蛋白激酶B信号通路活性与胰岛素敏感性，而外源性氧化应激可抵消这一胰岛素增敏效应。综上，本研究数据表明糖原自噬的表达水平处于动态调控之中，且其功能不仅限于持家过程，还可额外参与调控能量代谢与胰岛素信号通路。

缩写说明：AMP活化蛋白激酶（AMP-activated protein kinase, AMPK）；酸溶性代谢物（acid soluble metabolites, ASM）；环腺苷酸单磷酸（cyclic adenosine monophosphate, cAMP）；电脉冲刺激（electrical pulse stimulation, EPS）；羰基氰化物对三氟甲氧基苯腙（carbonyl cyanide-p-trifluoromethoxyphenylhydrazone, FCCP）；酸性α-葡糖苷酶（glucosidase, alpha, acid, GAA）；雷帕霉素靶蛋白激酶（mechanistic target of rapamycin kinase, mTOR）；烟酰胺腺嘌呤二核苷酸（nicotinamide adenine dinucleotide, NAD）；多聚ADP-核糖聚合酶家族（poly (ADP-ribose) polymerase family, PARP）；磷脂酰肌醇3-激酶（phosphoinositide 3-kinase, PI3K）；过氧化物酶体增殖物激活受体（peroxisome proliferator activated receptor, PPAR）；肌肉糖原磷酸化酶（muscle glycogen phosphorylase, PYGM）；淀粉结合域1（starch binding domain 1, STBD1）；转录因子EB（transcription factor EB, TFEB）。