Published in:
01-07-2018 | Research Letter
Lactate induces expression and secretion of fibroblast growth factor-21 by muscle cells
Authors:
Joan Villarroya, Laura Campderros, Francesc Ribas-Aulinas, Audrey Carrière, Louis Casteilla, Marta Giralt, Francesc Villarroya
Published in:
Endocrine
|
Issue 1/2018
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Excerpt
Fibroblast growth factor-21 (FGF21) is a hormonal factor involved in controlling glucose homeostasis and energy metabolism. Analogs of FGF21 are currently under investigation for potential use in metabolic diseases such as diabetes, dyslipidemia, and obesity [
1]. The liver is the main site of FGF21 expression and release into circulation. However, high levels of FGF21 have been found in patients with mitochondrial diseases, particularly neuromuscular diseases caused by primary mitochondrial DNA mutations; thus, FGF21 has been proposed as a potential biomarker of these diseases and is suggested to be responsible for some of the systemic alterations in patients [
2,
3]. Although the source of elevated FGF21 in patients with mitochondrial diseases that manifest in muscle is not fully known, mitochondrial DNA mutations or experimental mitochondrial perturbations in muscle lead to enhanced expression and release of FGF21 by skeletal muscle [
4,
5], a tissue not considered to be a substantial source of FGF21 in non-pathological conditions. In vitro studies have demonstrated that FGF21 expression and release by muscle cells are enhanced by mitochondrial stress, through a “mitochondrial retrograde signaling” induced by reactive oxygen species arising due to mitochondrial dysfunction [
6]. Serum FGF21 levels appear to have similar specificity, but higher sensitivity, as a biomarker of mitochondrial diseases, than lactate, a classical biomarker of mitochondrial disorders that manifest in muscle [
3]. Lactate originates through anaerobic metabolism of glucose in muscle; therefore, its production is enhanced when mitochondrial oxidative function is impaired. Lactate was recently reported to induce FGF21 expression and release in adipose tissue in experimental rodent models [
7]. Here, we investigated whether FGF21 is regulated by lactate in skeletal muscle cells and is, therefore, sensitive to the increased lactate levels that occur in mitochondrial diseases. …
