Itaconate and Its Derivatives Repress Early Myogenesis In Vitro and In Vivo.
Itaconate and Its Derivatives Repress Early Myogenesis In Vitro and In Vivo.
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DOI：
10.3389/fimmu.2022.748375
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发表时间：
2022
影响因子：
7.3
通讯作者：
Quinn MA
中科院分区：
文献类型：
--
作者：
Oh TS;Hutchins DC;Mainali R;Goslen KH;Quinn MA
三羧酸循环中间代谢物衣康酸盐由于其抗炎作用而作为潜在的抗微生物和自身免疫性疾病治疗而受到关注。虽然衣康酸及其衍生物为治疗炎性疾病提供了有吸引力的治疗选择，但免疫系统外的作用仍然有限，特别是在肌肉中。因此，我们决定确定衣康酸信号传导是否影响肌肉分化。利用成熟的C2 C12体外成肌模型，我们评估了衣康酸及其衍生物对肌肉分化的转录和蛋白质标志物以及线粒体功能的影响。我们发现衣康酸及其衍生物衣康酸二甲酯和衣康酸4-辛酯破坏分化介质诱导的肌生成。衣康酸盐的主要生物学作用是琥珀酸脱氢酶（SDH）抑制剂。我们发现SDH抑制剂丙二酸二甲酯和哈茨基吡啶酮表现出衣康酸的抗肌生成作用。此外，我们发现用外源性琥珀酸治疗导致肌生成钝化。总之，我们的数据表明衣康酸及其衍生物可能通过抑制SDH和随后的琥珀酸积累来干扰体外肌生成。我们还发现4-辛基衣康酸酯在体内抑制损伤诱导的MYOG表达。更重要的是，我们的研究结果表明衣康酸及其衍生物的治疗潜力可能是有限的，由于对肌生成的有害影响。
A Krebs cycle intermediate metabolite, itaconate, has gained attention as a potential antimicrobial and autoimmune disease treatment due to its anti-inflammatory effects. While itaconate and its derivatives pose an attractive therapeutic option for the treatment of inflammatory diseases, the effects outside the immune system still remain limited, particularly in the muscle. Therefore, we endeavored to determine if itaconate signaling impacts muscle differentiation. Utilizing the well-established C2C12 model of in vitro myogenesis, we evaluated the effects of itaconate and its derivatives on transcriptional and protein markers of muscle differentiation as well as mitochondrial function. We found itaconate and the derivatives dimethyl itaconate and 4-octyl itaconate disrupt differentiation media-induced myogenesis. A primary biological effect of itaconate is a succinate dehydrogenase (SDH) inhibitor. We find the SDH inhibitors dimethyl malonate and harzianopyridone phenocopie the anti-myogenic effects of itaconate. Furthermore, we find treatment with exogenous succinate results in blunted myogenesis. Together our data indicate itaconate and its derivatives interfere with in vitro myogenesis, potentially through inhibition of SDH and subsequent succinate accumulation. We also show 4-octyl itaconate suppresses injury-induced MYOG expression in vivo. More importantly, our findings suggest the therapeutic potential of itaconate, and its derivatives could be limited due to deleterious effects on myogenesis.