Low lysophosphatidylcholine induces skeletal muscle myopathy that is aggravated by high-fat diet feeding.
Low lysophosphatidylcholine induces skeletal muscle myopathy that is aggravated by high-fat diet feeding.
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DOI：
10.1096/fj.202101104r
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发表时间：
2021-10
期刊：
影响因子：
--
通讯作者：
Funai K
中科院分区：
文献类型：
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作者：
Ferrara PJ;Verkerke ARP;Maschek JA;Shahtout JL;Siripoksup P;Eshima H;Johnson JM;Petrocelli JJ;Mahmassani ZS;Green TD;McClung JM;Cox JE;Drummond MJ;Funai K
肥胖改变骨骼肌脂质组并促进肌病，但尚不清楚异常的肌肉脂质组是否有助于骨骼肌收缩力产生能力的降低。对小鼠骨骼肌的全面脂质组学分析显示，溶血磷脂酰胆碱（lyso-PC）（一类已知随肥胖而下调的脂质）的丰度与最大强直力产生之间存在非常强的正相关性。溶血-PC的水平主要由溶血-PC酰基转移酶3（LPCAT 3）调节，其酰化溶血-PC以形成磷脂酰胆碱。他莫昔芬诱导的骨骼肌特异性LPCAT 3过表达（LPCAT 3-MKI）足以降低标准食物饮食（SCD）和高脂饮食（HFD）喂养条件下的肌肉溶血PC含量。引人注目的是，离体骨骼肌力产生能力的评估显示，无论饮食如何，来自LPCAT 3-MKI小鼠的肌肉都较弱。力产生的缺陷在HFD喂养条件下更明显，其中与对照小鼠相比，来自LPCAT 3-MKI的肌肉的强直力产生低40%。这些观察结果的部分原因是IIa型和IIx型纤维的横截面积减少，以及在没有纤维化的情况下肌肉水肿的迹象。未来的研究将探讨LPCAT 3可能改变蛋白质周转以促进肌病的机制。
Obesity alters skeletal muscle lipidome and promotes myopathy, but it is unknown whether aberrant muscle lipidome contributes to the reduction in skeletal muscle contractile force-generating capacity. Comprehensive lipidomic analyses of mouse skeletal muscle revealed a very strong positive correlation between the abundance of lysophosphatidylcholine (lyso-PC), a class of lipids that is known to be downregulated with obesity, to maximal tetanic force production. The level of lyso-PC is regulated primarily by lyso-PC acyltransferase 3 (LPCAT3), which acylates lyso-PC to form phosphatidylcholine. Tamoxifen-inducible skeletal muscle-specific overexpression of LPCAT3 (LPCAT3-MKI) was sufficient to reduce muscle lyso-PC content in both standard chow diet (SCD) and high-fat diet (HFD)-fed conditions. Strikingly, assessment of skeletal muscle force-generating capacity ex vivo revealed that muscles from LPCAT3-MKI mice were weaker regardless of diet. Defects in force production were more apparent in HFD-fed condition, where tetanic force production was 40% lower in muscles from LPCAT3-MKI compared to that of control mice. These observations were partly explained by reductions in the cross-sectional area in type IIa and IIx fibers, and signs of muscle edema in the absence of fibrosis. Future studies will pursue the mechanism by which LPCAT3 may alter protein turnover to promote myopathy.