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ER-associated degradation maintains postnatal muscle hypertophy and systemic energy metabolism

ABSTRACT: The growth of skeletal muscle relies on a delicate equilibrium between protein synthesis and degradation; however, how proteostasis is managed in the endoplasmic reticulum is largely unknown. Here, we report that the SEL1L-HRD1 endoplasmic reticulum (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 significant reduction in overall body growth. In addition, myocyte-specific SEL1L deletion triggered a systemic reprogramming of metabolism characterized by improved glucose sensitivity, enhanced beiging 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE237194 | GEO | 2023/07/17

REPOSITORIES: GEO

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Transcriptomic responses to SEL1L-HRD1 ERAD deficiency in HEK293T cells and mouse brown adipose tissue

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Sel1L is Indispensable for Mammalian ERAD, ER Homeostasis and Survival

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The ER-Associated Degradation Adapter Protein Sel1L Regulates Triglyceride Metabolism via Lipoprotein Lipase

Project description:Sel1L is an adaptor protein for the E3 ligase Hrd1 in the endoplasmic reticulum-associated degradation (ERAD), but its physiological role in a cell-type-specific manner remains unclear. Here we show that mice with adipocyte-specific Sel1L deficiency are resistant to diet-induced obesity and exhibit postprandial hypertriglyceridemia. Mechanistically, our data demonstrate a critical requirement of Sel1L for the secretion of lipoprotein lipase (LPL), independently of its role in Hrd1-mediated ERAD and ER homeostasis. Further biochemical analyses revealed that Sel1L physically interacts and stabilizes the LPL maturation complex consisted of LPL and lipase-maturation factor 1 (LMF1). In the absence of Sel1L, LPL is retained in the ER and prone to the formation of protein aggregates, which are degraded by autophagy-mediated degradation. The Sel1L-mediated control of LPL secretion is seen in other LPL-expressing cell types as well such as cardiac muscle and macrophages. Thus, our study reports a novel role of Sel1L in LPL secretion and systemic lipid metabolism. Sel1Lflox/flox mice were crossed with adiponectin promoter driven Cre mice to create adipose tissue-specific Sel1L-/- mice. Male wildtype C57Bl/6 mice and adipose tissue-specific Sel1l-/- mice were fed a high fat diet (Research Diets D12492) for 5 weeks. Adipose tissue was excised and used for microarray analysis.

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Hepatic Sel1L-Hrd1 ER-Associated Degradation (ERAD) manages FGF21 levels and systemic metabolism via CREBH

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IRE1alpha is an endogenous substrate of endoplasmic reticulum-associated degradation

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Proteomic screens of SEL1L-HRD1 ER-associated degradation substrates reveal its vital importance in the biogenesis of glycosylphosphatidylinositol-anchored proteins

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