Muscle-specific ER-associated degradation maintains postnatal muscle hypertrophy and systemic energy metabolism.
Muscle-specific ER-associated degradation maintains postnatal muscle hypertrophy and systemic energy metabolism.
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DOI：
10.1172/jci.insight.170387
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发表时间：
2023-08-03
期刊：
影响因子：
8
通讯作者：
Qi, Ling
中科院分区：
文献类型：
--
作者：
Abdon, Benedict;Liang, Yusheng;Scheffer, Debora da Luz;Torres, Mauricio;Shrestha, Neha;Reinert, Rachel B.;Lu, You;Pederson, Brent;Bugarin-Lapuz, Amara;Kersten, Sander;Qi, Ling
骨骼肌的生长依赖于蛋白质合成和降解之间的微妙平衡;然而，如何在内质网（ER）中管理蛋白质稳态在很大程度上是未知的。在这里，我们报告说，SEL 1 L-HRD 1 ER相关降解（ERAD）复合物，降解ER中错误折叠蛋白的主要分子机制，对维持出生后肌肉生长和全身能量平衡至关重要。肌细胞特异性的SEL 1 L缺失使肌肉生长的肥大阶段变钝，导致在此发育期间肌肉质量的净零增益和整体身体生长减少30%。此外，肌细胞特异性SEL 1 L缺失引发了代谢的系统性重编程，其特征在于改善的葡萄糖敏感性、增强的脂肪细胞褐变和对饮食诱导的肥胖的抵抗。这些作用部分由肌因子FGF 21的上调介导。这些发现强调了SEL 1 L-HRD 1 ERAD活性在骨骼肌细胞中对出生后肌肉生长的关键作用，以及其在维持全身能量平衡中的生理整合。
The growth of skeletal muscle relies on a delicate equilibrium between protein synthesis and degradation; however, how proteostasis is managed in the endoplasmic reticulum (ER) is largely unknown. Here, we report that the SEL1L-HRD1 ER-associated degradation (ERAD) complex, the primary molecular machinery that degrades misfolded proteins in the ER, is vital to maintain postnatal muscle growth and systemic energy balance. Myocyte-specific SEL1L deletion blunts the hypertrophic phase of muscle growth, resulting in a net zero gain of muscle mass during this developmental period and a 30% reduction in overall body growth. In addition, myocyte-specific SEL1L deletion triggered a systemic reprogramming of metabolism characterized by improved glucose sensitivity, enhanced beigeing of adipocytes, and resistance to diet-induced obesity. These effects were partially mediated by the upregulation of the myokine FGF21. These findings highlight the pivotal role of SEL1L-HRD1 ERAD activity in skeletal myocytes for postnatal muscle growth, and its physiological integration in maintaining whole-body energy balance.
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