Muscle mitochondrial stress adaptation operates independently of endogenous FGF21 action

Abstract

ObjectiveFibroblast growth factor 21 (FGF21) was recently discovered as stress-induced myokine during mitochondrial disease and proposed as key metabolic mediator of the integrated stress response (ISR) presumably causing systemic metabolic improvements. Curiously, the precise cell-non-autonomous and cell-autonomous relevance of endogenous FGF21 action remained poorly understood.MethodsWe made use of the established UCP1 transgenic (TG) mouse, a model of metabolic perturbations made by a specific decrease in muscle mitochondrial efficiency through increased respiratory uncoupling and robust metabolic adaptation and muscle ISR-driven FGF21 induction. In a cross of TG with Fgf21-knockout (FGF21−/−) mice, we determined the functional role of FGF21 as a muscle stress-induced myokine under low and high fat feeding conditions.ResultsHere we uncovered that FGF21 signaling is dispensable for metabolic improvements evoked by compromised mitochondrial function in skeletal muscle. Strikingly, genetic ablation of FGF21 fully counteracted the cell-non-autonomous metabolic remodeling and browning of subcutaneous white adipose tissue (WAT), together with the reduction of circulating triglycerides and cholesterol. Brown adipose tissue activity was similar in all groups. Remarkably, we found that FGF21 played a negligible role in muscle mitochondrial stress-related improved obesity resistance, glycemic control and hepatic lipid homeostasis. Furthermore, the protective cell-autonomous muscle mitohormesis and metabolic stress adaptation, including an increased muscle proteostasis via mitochondrial unfolded protein response (UPRmt) and amino acid biosynthetic pathways did not require the presence of FGF21.ConclusionsHere we demonstrate that although FGF21 drives WAT remodeling, the adaptive pseudo-starvation response under elevated muscle mitochondrial stress conditions operates independently of both WAT browning and FGF21 action. Thus, our findings challenge FGF21 as key metabolic mediator of the mitochondrial stress adaptation and powerful therapeutic target during muscle mitochondrial disease.

Mitochondrial energy deficiency leads to hyperproliferation of skeletal muscle mitochondria and enhanced insulin sensitivity

“…This similarity is further enhanced, as the knock-out of the Fgf21 gene in Tg-HAS-UCP1 mice did not abrogate their tendency to hypoglycemia and increased insulin sensitivity (35).…”

Impaired Mitochondrial Fat Oxidation Induces FGF21 in Muscle

“…Energy deficit caused by respiratory chain deficiencies leads to mitochondrial myopathy and increased FGF21 production in mice and humans (Suomalainen et al, 2011; Tyynismaa et al, 2010). In another model of mitochondrial inefficiency, muscle specific over expression of UCP-1 causes FGF21 upregulation in skeletal muscle (Keipert et al, 2014; Ost et al, 2016). Dysregulation of lipid delivery to mitochondria by either overexpression of perilipin 5 (Harris et al, 2015) or deletion of the lipase ATGL (Brahma et al, 2014), leads to FGF21 induction in skeletal muscle or heart, respectively.…”

“…There are a number of studies demonstrating the induction of FGF21 requires an activating transcription factor 4 (ATF4)-dependent mechanism (De Sousa-Coelho et al, 2012; Kim et al, 2013a; Kim et al, 2013b; Ost et al, 2016; Tyynismaa et al, 2010). We were surprised to see no changes in Aft4 mRNA or protein levels in Cpt1b m−/− mice.…”

“…However, under myopathic conditions resulting from deficiencies in the mitochondrial respiratory chain FGF21 can be secreted from skeletal muscle (Kim et al, 2013b; Tyynismaa et al, 2010). Also the transgenic overexpression of Akt1 (Izumiya et al, 2008), Perilipin-5 (Harris et al, 2015), and UCP1(Keipert et al, 2014; Ost et al, 2016) in skeletal muscle induces FGF21 secretion. The skeletal muscle-specific ablation of autophagy-related 7 (Atg7) leads to an autophagy deficiency and mitochondrial dysfunction and increases FGF21 in muscle (Kim et al, 2013b; Tyynismaa et al, 2010).…”

Energy status and ovarian follicular development

“…The phenotype resulting from the uncoupling of muscle mitochondria can be considered as skeletalmuscle semi-starvation. Indeed, in the UCP1-TG mice there is an energy drain towards skeletal muscle tissue to provide this tissue with sufficient energy [124,144]. The increased energy expenditure, the increased food intake and the maintenance of adiposity, support the assumption that nutrient flux is altered in these mice.…”