title: Skeletal muscle increases FGF21 expression in mitochondrial disorders to compensate for energy metabolic insufficiency by activating the mTOR-YY1-PGC1α pathway.
abstract: Fibroblast growth factor 21 (FGF21) is a growth factor with pleiotropic effects on regulating lipid and glucose metabolism. Its expression is increased in skeletal muscle of mice and humans with mitochondrial disorders. However, the effects of FGF21 on skeletal muscle in response to mitochondrial respiratory chain deficiency are largely unknown. Here we demonstrate that the increased expression of FGF21 is a compensatory response to respiratory chain deficiency. The mRNA and protein levels of FGF21 were robustly raised in skeletal muscle from patients with mitochondrial myopathy or MELAS. The mammalian target of rapamycin (mTOR) phosphorylation levels and its downstream targets, Yin Yang 1 (YY1) and peroxisome proliferator-activated receptor γ, coactivator 1α (PGC-1α), were increased by FGF21 treatment in C2C12 myoblasts. Activation of the mTOR-YY1-PGC1α pathway by FGF21 in myoblasts regulated energy homeostasis as demonstrated by significant increases in intracellular ATP synthesis, oxygen consumption rate, activity of citrate synthase, glycolysis, mitochondrial DNA copy number, and induction of the expression of key energy metabolic genes. The effects of FGF21 on mitochondrial function required phosphoinositide 3-kinase (PI3K), which activates mTOR. Inhibition of PI3K, mTOR, YY1, and PGC-1α activities attenuated the stimulating effects of FGF21 on intracellular ATP levels and mitochondrial gene expression. Our findings revealed that mitochondrial respiratory chain deficiency elicited a compensatory response in skeletal muscle by increasing the FGF21 expression levels in muscle, which resulted in enhanced mitochondrial function through an mTOR-YY1-PGC1α-dependent pathway in skeletal muscle.
authors.affiliation: Laboratory of Neuromuscular Disorders and Department of Neurology, Qilu Hospital, Shandong University, Jinan, 250012, China.
authors.forename: Kunqian
authors.initials: K
authors.lastname: Ji
authors.affiliation: Laboratory of Neuromuscular Disorders and Department of Neurology, Qilu Hospital, Shandong University, Jinan, 250012, China.
authors.forename: Jinfan
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Laboratory of Neuromuscular Disorders and Department of Neurology, Qilu Hospital, Shandong University, Jinan, 250012, China.
authors.forename: Jingwei
authors.initials: J
authors.lastname: Lv
authors.affiliation: Laboratory of Neuromuscular Disorders and Department of Neurology, Qilu Hospital, Shandong University, Jinan, 250012, China.
authors.forename: Jingwen
authors.initials: J
authors.lastname: Xu
authors.affiliation: Laboratory of Neuromuscular Disorders and Department of Neurology, Qilu Hospital, Shandong University, Jinan, 250012, China.
authors.forename: Xinbo
authors.initials: X
authors.lastname: Ji
authors.affiliation: Laboratory of Neuromuscular Disorders and Department of Neurology, Qilu Hospital, Shandong University, Jinan, 250012, China.
authors.forename: Yue-Bei
authors.initials: YB
authors.lastname: Luo
authors.affiliation: Laboratory of Neuromuscular Disorders and Department of Neurology, Qilu Hospital, Shandong University, Jinan, 250012, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Laboratory of Neuromuscular Disorders and Department of Neurology, Qilu Hospital, Shandong University, Jinan, 250012, China.
authors.forename: Yuying
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Laboratory of Neuromuscular Disorders and Department of Neurology, Qilu Hospital, Shandong University, Jinan, 250012, China; Key Laboratory for Experimental Teratology of the Ministry of Education, Brain Science Research Institute, Department of Neurology, Qilu Hospital, Shandong University, Jinan, 250012, China. Electronic address: chuanzhuyan@163.com.
authors.forename: Chuanzhu
authors.initials: C
authors.lastname: Yan
mesh_terms: D000818:Animals; D002460:Cell Line; D004734:Energy Metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D006801:Humans; D017241:MELAS Syndrome / Q000378:metabolism*; D051379:Mice; D008931:Mitochondria, Muscle / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D010084:Oxidation-Reduction; D010101:Oxygen Consumption; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D050986:YY1 Transcription Factor / Q000378:metabolism
chemical_list: C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors; D050986:YY1 Transcription Factor; C494698:YY1 protein, human; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: Fibroblast growth factor 21; Free radicals; Mitochondrial diseases; Mitochondrial function; Oxidative stress; Skeletal muscle