Maschari Dominic, Saxena Gunjan, Law Timothy D, Walsh Erin, Campbell Mason C, Consitt Leslie A
College of Health Sciences and Professions, Ohio University, Athens, OH, United States.
Department of Biomedical Sciences, Ohio University, Athens, OH, United States.
Front Physiol. 2022 Aug 30;13:951390. doi: 10.3389/fphys.2022.951390. eCollection 2022.
Elevated circulating lactate has been associated with obesity and insulin resistance. The aim of the current study was to determine if lactate-induced lysine lactylation (kla), a post-translational modification, was present in human skeletal muscle and related to insulin resistance. Fifteen lean (Body Mass Index: 22.1 ± 0.5 kg/m) and fourteen obese (40.6 ± 1.4 kg/m) adults underwent a muscle biopsy and 2-h oral glucose tolerance test. Skeletal muscle lactylation was increased in obese compared to lean females (19%, < 0.05) and associated with insulin resistance (r = 0.37, < 0.05) in the whole group. Skeletal muscle lactylation levels were significantly associated with markers of anaerobic metabolism (plasma lactate and skeletal muscle lactate dehydrogenase [LDH], < 0.05) and negatively associated with markers of oxidative metabolism (skeletal muscle cytochrome c oxidase subunit 4 and Complex I [pyruvate] OXPHOS capacity, < 0.05). Treatment of primary human skeletal muscle cells (HSkMC) with sodium lactate for 24 h increased protein lactylation and IRS-1 serine 636 phosphorylation in a similar dose-dependent manner ( < 0.05). Inhibition of glycolysis (with 2-deoxy-d-glucose) or LDH-A (with sodium oxamate or LDH-A siRNA) for 24 h reduced HSkMC lactylation which paralleled reductions in culture media lactate accumulation. This study identified the existence of a lactate-derived post-translational modification in human skeletal muscle and suggests skeletal muscle lactylation could provide additional insight into the regulation of skeletal muscle metabolism, including insulin resistance.
循环乳酸水平升高与肥胖和胰岛素抵抗有关。本研究的目的是确定乳酸诱导的赖氨酸乳酰化（kla，一种翻译后修饰）是否存在于人类骨骼肌中，并与胰岛素抵抗相关。15名瘦人（体重指数：22.1±0.5kg/m²）和14名肥胖者（40.6±1.4kg/m²）成年人接受了肌肉活检和2小时口服葡萄糖耐量试验。与瘦女性相比，肥胖女性的骨骼肌乳酰化增加（19%，P<0.05），且在整个研究组中与胰岛素抵抗相关（r=0.37，P<0.05）。骨骼肌乳酰化水平与无氧代谢标志物（血浆乳酸和骨骼肌乳酸脱氢酶[LDH]，P<0.05）显著相关，与氧化代谢标志物（骨骼肌细胞色素c氧化酶亚基4和复合物I[丙酮酸]氧化磷酸化能力，P<0.05）呈负相关。用乳酸钠处理原代人骨骼肌细胞（HSkMC）24小时，以类似的剂量依赖性方式增加了蛋白质乳酰化和IRS-1丝氨酸636磷酸化（P<0.05）。抑制糖酵解（用2-脱氧-d-葡萄糖）或LDH-A（用草酸钠或LDH-A siRNA）24小时可降低HSkMC乳酰化，这与培养基中乳酸积累的减少相平行。本研究确定了人类骨骼肌中存在一种源自乳酸的翻译后修饰，并表明骨骼肌乳酰化可为骨骼肌代谢调节（包括胰岛素抵抗）提供更多见解。
