AMPK regulates lipid accumulation in skeletal muscle cells through FTO-dependent demethylation of N6-methyladenosine

Wu, Wen‐Jer; Feng, Jie; Jiang, Dandan; Zhou, Xin; Jiang, Qin; Cai, Min; Wang, Xinxia; Shan, Tizhong; Wang, Yizhen

doi:10.1038/srep41606

Cited by 90 publications

(84 citation statements)

References 57 publications

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“…AMPK (AMP-activated protein kinase) is an essential part of skeletal muscle lipid metabolism and is the major cellular energy sensor. In skeletal muscle cells AMPK reduces mRNA m6A methylation and lipid accumulation by FTO-dependent demethylation at the molecular level 43 .…”

Section: Discussionmentioning

confidence: 99%

Replication of FTO Gene associated with lean mass in a Meta-Analysis of Genome-Wide Association Studies

Ran

Jiang

Xiao

et al. 2020

Sci Rep

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Sarcopenia is characterized by low skeletal muscle, a complex trait with high heritability. With the dramatically increasing prevalence of obesity, obesity and sarcopenia occur simultaneously, a condition known as sarcopenic obesity. fat mass and obesity-associated (fto) gene is a candidate gene of obesity. to identify associations between lean mass and fto gene, we performed a genome-wide association study (GWAS) of lean mass index (LMI) in 2207 unrelated Caucasian subjects and replicated major findings in two replication samples including 6,004 unrelated Caucasian and 38,292 unrelated Caucasian. We found 29 single nucleotide polymorphisms (SNPs) in FTO significantly associated with sarcopenia (combined p-values ranging from 5.92 × 10 −12 to 1.69 × 10 −9 ). potential biological functions of SNPs were analyzed by HaploReg v4.1, RegulomeDB, GTEx, IMPC and STRING. Our results provide suggestive evidence that fto gene is associated with lean mass.Sarcopenia is a complex disease described as the age-associated loss of skeletal muscle mass, strength and function impairment 1,2 . The low skeletal muscle mass will lead to many public health problems such as sarcopenia, osteoporosis and increased mortality 3,4 , especially in the elderly. Skeletal muscle is heritable with heritability estimates of 30-85% for muscle strength and 45-90% for muscle mass 5 . Although there are many genetic researches have shown some SNPs and copy number variants (CNVs) associated with lean mass 6-14 , the majority of specific genes underlying the variations in low lean body mass (LBM) are still unknown. And sarcopenia can be predicted by LMI 15 .FTO gene is proved the association with fat mass, which contributes to human obesity [16][17][18][19][20][21] . According to many vivo studies using FTO overexpression or knockout mouse models, FTO gene can cause abnormal adipose tissues and body mass, implying a pivotal role of FTO in adipogenesis and energy homeostasis [22][23][24][25] . But the exact biological functions of this gene are unknown yet. In recent researches, FTO gene is proved the association with lean mass 22,23,[26][27][28][29][30][31] . Zillikens et al. reported a series of SNPs of FTO associated with LBM and appendicular lean mass (ALM) 30 . In our study, we performed a GWAS to identify the associations between FTO and LMI in 2,207 unrelated Caucasians (516 men and 1,691 women). Then we replicated our findings in two replication samples, including 6,004 unrelated Caucasians and 38,292 unrelated Caucasians subjects 30 . Methods ethic statement. This study was approved by institutional review boards of Creighton University and theUniversity of Missouri-Kansas City. Before entering the study, all subjects provide written informed consent documents. The methods carried out in accordance with the approved study protocol.Discovery sample. The discovery sample consisted of 2,207 unrelated Caucasian subjects of European ancestry that were recruited in Midwestern U.S. (Kansas City, Missouri and Omaha, Nebraska). All discovery subjects com...

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Section: Discussionmentioning

confidence: 99%

Replication of FTO Gene associated with lean mass in a Meta-Analysis of Genome-Wide Association Studies

Ran

Jiang

Xiao

et al. 2020

Sci Rep

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“…Fat tissue obesity is a nucleic acid demethylase that controls the expression of genes involved in energy metabolism. Its overexpression has been shown to cause intracellular lipid accumulation in skeletal muscle cells and increased white adipose tissue . Interestingly, proteome analysis also revealed an activation of the Wnt/β‐catenin pathway in both groups, which is known to have a dual function as it is involved either in muscle regeneration or in fibrosis .…”

Section: Discussionmentioning

confidence: 99%

Muscle wasting in patients with end‐stage renal disease or early‐stage lung cancer: common mechanisms at work

Aniort

Stella

Philipponnet

et al. 2019

J cachexia sarcopenia muscle

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Background Loss of muscle mass worsens many diseases such as cancer and renal failure, contributes to the frailty syndrome, and is associated with an increased risk of death. Studies conducted on animal models have revealed the preponderant role of muscle proteolysis and in particular the activation of the ubiquitin proteasome system (UPS). Studies conducted in humans remain scarce, especially within renal deficiency. Whether a shared atrophying programme exists independently of the nature of the disease remains to be established. The aim of this work was to identify common modifications at the transcriptomic level or the proteomic level in atrophying skeletal muscles from cancer and renal failure patients. Methods Muscle biopsies were performed during scheduled interventions in early‐stage (no treatment and no detectable muscle loss) lung cancer (LC), chronic haemodialysis (HD), or healthy (CT) patients ( n = 7 per group; 86% male; 69.6 ± 11.4, 67.9 ± 8.6, and 70.2 ± 7.9 years P > 0.9 for the CT, LC, and HD groups, respectively). Gene expression of members of the UPS, autophagy, and apoptotic systems was measured by quantitative real‐time PCR. A global analysis of the soluble muscle proteome was conducted by shotgun proteomics for investigating the processes altered. Results We found an increased expression of several UPS and autophagy‐related enzymes in both LC and HD patients. The E3 ligases MuRF1 (+56 to 78%, P < 0.01), MAFbx (+68 to 84%, P = 0.02), Hdm2 (+37 to 59%, P = 0.02), and MUSA1/Fbxo30 (+47 to 106%, P = 0.01) and the autophagy‐related genes CTPL (+33 to 47%, P = 0.03) and SQSTM1 (+47 to 137%, P < 0.01) were overexpressed. Mass spectrometry identified >1700 proteins, and principal component analysis revealed three differential proteomes that matched to the three groups of patients. Orthogonal partial least square discriminant analysis created a model, which distinguished the muscles of diseased patients (LC or HD) from those of CT subjects. Proteins that most contributed to the model were selected. Functional analysis revealed up to 238 proteins belonging to nine metabolic processes (inflammatory response, proteolysis, cytoskeleton organization, glucose metabolism, muscle contraction, oxidant detoxification, energy metabolism, fatty acid metabolism, and extracellular matrix) involved in and/or altered by the atrophying programme in both LC and HD patients. This was confirmed by a co‐expression network analysis. Conclusions We were able to identify highly similar modifications of several metabolic pathways in patients exhibiting diseases with different aetiologies (early‐stage LC vs. long‐term renal failure). This strongly suggests that a common atrophying programme e...

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“…For instance, decreased AMPK activity in the hypothalamus mediates the central GLP‐1 actions on BAT thermogenesis and browning of white adipocytes . Peripherally, AMPK activation in skeletal muscle and the liver inhibits the biosynthesis and accumulation of fatty acid and cholesterol, and enhances lipid oxidation, muscle glucose uptake and caloric intake, effects that are promoted by several adipokines such as leptin and adiponectin . In this regard, intramuscular injection of the GLP1 receptor agonist exendin‐4 (1 μg kg −1 ) was able to increase the expression of pAMPK and UCP1 in the muscle of diet‐induced obese mice .…”

Section: Discussionmentioning

confidence: 99%

Cooperative role of the glucagon‐like peptide‐1 receptor and β3‐adrenergic‐mediated signalling on fat mass reduction through the downregulation of PKA/AKT/AMPK signalling in the adipose tissue and muscle of rats

et al. 2017

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AMPK regulates lipid accumulation in skeletal muscle cells through FTO-dependent demethylation of N6-methyladenosine

Cited by 90 publications

References 57 publications

Replication of FTO Gene associated with lean mass in a Meta-Analysis of Genome-Wide Association Studies

Replication of FTO Gene associated with lean mass in a Meta-Analysis of Genome-Wide Association Studies

Muscle wasting in patients with end‐stage renal disease or early‐stage lung cancer: common mechanisms at work

Cooperative role of the glucagon‐like peptide‐1 receptor and β3‐adrenergic‐mediated signalling on fat mass reduction through the downregulation of PKA/AKT/AMPK signalling in the adipose tissue and muscle of rats

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