Skeletal muscle increases FGF21 expression in mitochondrial disorders to compensate for energy metabolic insufficiency by activating the mTOR-YY1-PGC1α pathway

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.