Valentine William J, Mostafa Sherif A, Tokuoka Suzumi M, Hamano Fumie, Inagaki Natsuko F, Nordin Joel Z, Motohashi Norio, Kita Yoshihiro, Aoki Yoshitsugu, Shimizu Takao, Shindou Hideo
Department of Molecular Therapy, National Center for Neurology and Psychiatry (NCNP), National Institute of Neuroscience, Kodaira, Tokyo, Japan.
Department of Lipid Signaling, National Center for Global Health and Medicine (NCGM), Shinjuku-ku, Japan.
Front Physiol. 2022 Jan 12;12:698166. doi: 10.3389/fphys.2021.698166. eCollection 2021.
In Duchenne muscular dystrophy (DMD), lack of dystrophin increases the permeability of myofiber plasma membranes to ions and larger macromolecules, disrupting calcium signaling and leading to progressive muscle wasting. Although the biological origin and meaning are unclear, alterations of phosphatidylcholine (PC) are reported in affected skeletal muscles of patients with DMD that may include higher levels of fatty acid (FA) 18:1 chains and lower levels of FA 18:2 chains, possibly reflected in relatively high levels of PC 34:1 (with 16:0_18:1 chain sets) and low levels of PC 34:2 (with 16:0_18:2 chain sets). Similar PC alterations have been reported to occur in the mouse model of DMD. However, altered ratios of PC 34:1 to PC 34:2 have been variably reported, and we also observed that PC 34:2 levels were nearly equally elevated as PC 34:1 in the affected muscles. We hypothesized that experimental factors that often varied between studies; including muscle types sampled, mouse ages, and mouse diets; may strongly impact the PC alterations detected in dystrophic muscle of mice, especially the PC 34:1 to PC 34:2 ratios. In order to test our hypothesis, we performed comprehensive lipidomic analyses of PC and phosphatidylethanolamine (PE) in several muscles (extensor digitorum longus, gastrocnemius, and soleus) and determined the -specific alterations. The alterations in PC 34:1 and PC 34:2 were closely monitored from the neonate period to the adult, and also in mice raised on several diets that varied in their fats. PC 34:1 was naturally high in neonate's muscle and decreased until age ∼3-weeks (disease onset age), and thereafter remained low in WT muscles but was higher in regenerated muscles. Among the muscle types, soleus showed a distinctive phospholipid pattern with early and diminished alterations. Diet was a major factor to impact PC 34:1/PC 34:2 ratios because -specific alterations of PC 34:2 but not PC 34:1 were strictly dependent on diet. Our study identifies high PC 34:1 as a consistent biochemical feature of regenerated -muscle and indicates nutritional approaches are also effective to modify the phospholipid compositions.
在杜兴氏肌营养不良症(DMD)中,肌营养不良蛋白的缺乏会增加肌纤维质膜对离子和更大分子的通透性,破坏钙信号传导并导致进行性肌肉萎缩。尽管其生物学起源和意义尚不清楚,但据报道,DMD患者受影响的骨骼肌中磷脂酰胆碱(PC)发生了改变,可能包括较高水平的脂肪酸(FA)18:1链和较低水平的FA 18:2链,这可能反映在相对较高水平的PC 34:1(具有16:0_18:1链组)和较低水平的PC 34:2(具有16:0_18:2链组)上。据报道,在DMD小鼠模型中也发生了类似的PC改变。然而,关于PC 34:1与PC 34:2的改变比例的报道各不相同,而且我们还观察到在受影响的肌肉中PC 34:2的水平与PC 34:1几乎同样升高。我们推测,研究之间经常变化的实验因素,包括所采集的肌肉类型、小鼠年龄和小鼠饮食,可能会强烈影响在营养不良小鼠肌肉中检测到的PC改变,特别是PC 34:1与PC 34:2的比例。为了验证我们的假设,我们对几块肌肉(趾长伸肌、腓肠肌和比目鱼肌)中的PC和磷脂酰乙醇胺(PE)进行了全面脂质组分析,并确定了具体的改变。从新生儿期到成年期,以及在几种脂肪含量不同的饮食喂养的小鼠中,密切监测PC 34:1和PC 34:2的改变。PC 34:1在新生儿肌肉中天然含量较高,直到约3周龄(疾病发病年龄)时下降,并在之后在野生型肌肉中保持较低水平,但在再生肌肉中较高。在肌肉类型中,比目鱼肌显示出独特的磷脂模式,其改变较早且程度较轻。饮食是影响PC 34:1/PC 34:2比例的主要因素,因为PC 34:2而非PC 34:1的具体改变严格依赖于饮食。我们的研究确定高PC 34:1是再生肌肉的一个一致的生化特征,并表明营养方法也能有效改变磷脂组成。