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CPT1A 的过表达破坏了肌肉干细胞的维持和再生功能。

Overexpression of CPT1A disrupts the maintenance and regenerative function of muscle stem cells.

机构信息

Department of Animal Sciences, Purdue University, West Lafayette, Indiana, USA.

Department of Animal Sciences, University of Florida, Gainesville, Florida, USA.

出版信息

FASEB J. 2024 Oct 15;38(19):e70071. doi: 10.1096/fj.202400947R.

DOI:10.1096/fj.202400947R
PMID:39382025
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11486317/
Abstract

The skeletal muscle satellite cells (SCs) mediate regeneration of myofibers upon injury. As they switch from maintenance (quiescence) to regeneration, their relative reliance on glucose and fatty acid metabolism alters. To explore the contribution of mitochondrial fatty acid oxidation (FAO) pathway to SCs and myogenesis, we examined the role of carnitine palmitoyltransferase 1A (CPT1A), the rate-limiting enzyme of FAO. CPT1A is highly expressed in quiescent SCs (QSCs) compared with activated and proliferating SCs, and its expression level decreases during myogenic differentiation. Myod1-driven overexpression (OE) of Cpt1a in embryonic myoblasts (Cpt1a) reduces muscle weight, grip strength, and contractile force without affecting treadmill endurance of adult mice. Adult Cpt1a mice have reduced number of SC, impairing muscle regeneration and promoting lipid infiltration. Similarly, Pax7-driven, tamoxifen-inducible Cpt1a-OE in QSCs of adult muscles (Cpt1a) leads to depletion of SCs and compromises muscle regeneration. The reduced proliferation of Cpt1a-OE SCs is associated with elevated level of acyl-carnitine, and acyl-carnitine treatment impedes proliferation of wildtype SCs. These findings indicate that aberrant level of CPT1A elevates acyl-carnitine to impair the maintenance, proliferation and regenerative function of SCs.

摘要

骨骼肌卫星细胞 (SCs) 在损伤后介导肌纤维的再生。当它们从维持 (静止) 状态切换到再生状态时，它们对葡萄糖和脂肪酸代谢的相对依赖程度发生改变。为了探索线粒体脂肪酸氧化 (FAO) 途径对 SC 和肌发生的贡献，我们研究了肉碱棕榈酰转移酶 1A (CPT1A) 的作用，CPT1A 是 FAO 的限速酶。与激活和增殖的 SC 相比，CPT1A 在静止的 SC (QSCs) 中高度表达，并且在肌发生分化过程中其表达水平降低。Myod1 驱动的 Cpt1a 在胚胎成肌细胞中的过表达 (OE) (Cpt1a) 降低了肌肉重量、握力和收缩力，而不影响成年小鼠的跑步机耐力。成年 Cpt1a 小鼠的 SC 数量减少，损害肌肉再生并促进脂质浸润。同样，Pax7 驱动的、他莫昔芬诱导的成年肌肉 QSCs 中的 Cpt1a-OE (Cpt1a) 导致 SC 耗竭，并损害肌肉再生。Cpt1a-OE SCs 的增殖减少与酰基辅酶 A 水平升高有关，并且酰基辅酶 A 处理会阻碍野生型 SCs 的增殖。这些发现表明，异常的 CPT1A 水平会升高酰基辅酶 A，从而损害 SC 的维持、增殖和再生功能。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b22/11486317/3f8b91e5bce9/nihms-2023393-f0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b22/11486317/b4691be84cf4/nihms-2023393-f0002.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b22/11486317/60d1e9617d6e/nihms-2023393-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b22/11486317/827839d6c1cf/nihms-2023393-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b22/11486317/c487e089e31a/nihms-2023393-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b22/11486317/608238cf2e0b/nihms-2023393-f0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b22/11486317/3f8b91e5bce9/nihms-2023393-f0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b22/11486317/b4691be84cf4/nihms-2023393-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b22/11486317/42003eb349d4/nihms-2023393-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b22/11486317/3c7c40aba56c/nihms-2023393-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b22/11486317/373ea6fce80f/nihms-2023393-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b22/11486317/60d1e9617d6e/nihms-2023393-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b22/11486317/827839d6c1cf/nihms-2023393-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b22/11486317/c487e089e31a/nihms-2023393-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b22/11486317/608238cf2e0b/nihms-2023393-f0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b22/11486317/3f8b91e5bce9/nihms-2023393-f0010.jpg

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