Angiotensin-converting enzyme 2 regulates endoplasmic reticulum stress and mitochondrial function to preserve skeletal muscle lipid metabolism

Xi Cao,Xiu Tuo,Yi-Chen Zhang,Jin-Kui Yang,Li-Ni Song,Zhong Xin,Xin-Meng Lu,Zhi-Qiang Cheng,Jing-Yi Liu

doi:10.1186/s12944-019-1145-x

Abstract

ObjectiveEndoplasmic reticulum (ER) stress and mitochondrial function affected intramuscular fat accumulation. However, there is no clear evident on the effect of the regulation of ER stress and mitochondrial function by Angiotensin-converting enzyme 2 (ACE2) on the prevention of intramuscular fat metabolism. We investigated the effects of ACE2 on ER stress and mitochondrial function in skeletal muscle lipid metabolism.MethodsThe triglyceride (TG) content in skeletal muscle of ACE2 knockout mice and Ad-ACE2-treated db/db mice were detected by assay kits. Meanwhile, the expression of lipogenic genes (ACCα, SREBP-1c, LXRα, CPT-1α, PGC-1α and PPARα), ER stress and mitochondrial function related genes (GRP78, eIF2α, ATF4, BCL-2, and SDH6) were analyzed by RT-PCR. Lipid metabolism, ER stress and mitochondrial function related genes were analyzed by RT-PCR in ACE2-overexpression C2C12 cell. Moreover, the IKKβ/NFκB/IRS-1 pathway was determined using lysate sample from skeletal muscle of ACE2 knockout mice.ResultsACE2 deficiency in vivo is associated with increased lipid accumulation in skeletal muscle. The ACE2 knockout mice displayed an elevated level of ER stress and mitochondrial dysfunctions in skeletal muscle. In contrast, activation of ACE2 can ameliorate ER stress and mitochondrial function, which slightly accompanied by reduced TG content and down-regulated the expression of skeletal muscle lipogenic proteins in the db/db mice. Additionally, ACE2 improved skeletal muscle lipid metabolism and ER stress genes in the C2C12 cells. Mechanistically, endogenous ACE2 improved lipid metabolism through the IKKβ/NFκB/IRS-1 pathway in skeletal muscle.ConclusionsACE2 was first reported to play a notable role on intramuscular fat regulation by improving endoplasmic reticulum and mitochondrial function. This study may provide a strategy for treating insulin resistance in skeletal muscle.

Highlights

Intramuscular fat is an indispensable energy source for skeletal muscle
We investigated the role of Angiotensin-converting enzyme 2 (ACE2) in regulating intramuscular fat and its possible behavior on endoplasmic reticulum and mitochondrial function to clarify the function of ACE2 in metabolism and provided a potential target for insulin resistance prevention in skeletal muscle
The mRNA levels of fatty acid oxidation-related genes, including PPARγ coactivator 1α (PGC-1α), peroxisome proliferator-activated receptor alpha (PPARα), and medium chain acy -CoA dehydrogenase (MCAD) were down-regulated, and little change was observed in PPAR gamma (PPARγ) and CPT-1α in the skeletal muscle of the ACE2 knockout mice (ACE2−/y) mice (Fig. 1d)

Summary

Introduction

Intramuscular fat is an indispensable energy source for skeletal muscle. These lipids play pivotal roles in metabolism for skeletal muscle and for the entire body. Excess lipid accumulation and impairment in mitochondrial function have been considered as putative mechanisms for the pathogenesis of skeletal muscle insulin resistance. Β-oxidation of fatty acids (FAs) is linked to ATP production, mitochondrial respiration [3], and redox balance [4]. Muscle mitochondria regulate the transport and β-oxidation flux of long-chain fatty acids [5]. Mitochondrial deficiency as the cause of impaired fatty acid oxidation capacity and skeletal muscle fat accumulation, leading to the mitochondrial-driven ‘lipotoxicity’ hypothesis of insulin resistance [6]

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