Skeletal muscle mitochondrial uncoupling induces a metabolic rescue cycle involving FGF21 as a myokine

Ectopic expression of uncoupling protein 1 (UCP1) in skeletal muscle (SM) improves whole body energy metabolism and promotes longevity in transgenic mice (UCP1-TG). However, exact physiological mechanisms underlying this metabolic improvement have not yet been resolved. Here, we show that uncoupling in SM induces Fgf21 expression using UCP1-TG mice, resulting in >5 fold elevated circulating FGF21 levels. UCP1-TG mice display maintained muscle function and morphology but reduced muscle mass. In muscle, the autophagic machinery is activated, which is reflected by increased intracellular eIF2alpha/Atf4. Moreover, ER-stress markers such as the Chop, Atf5, Atf6 and Gadd34 are induced. Furthermore, amino acid stress pathways are induced, as shown by increased amino acid response elements (AAREs), which correlate with Fgf21 expression. The serine/glycine biosynthesis pathway was strongly up-regulated in SM of UCP1-TG mice. In addition, gene expression of glucose transporter 1 (Glut1) as well as basal glucose uptake are increased in transgenic mice SM. Accelerated flux through this alternative glycolysis pathway may help SM to adapt to chronic metabolic stress. Strikingly, ß-klotho, a required co-factor for global FGF21 action, is increased in skeletal muscle, liver and white adipose tissue (WAT) of UCP1-TG mice, leading to increased futile cycle (increased lipogenesis/lipolysis) in WAT depots and increased hepatic gluconeogenesis. We conclude that remote metabolic improvements caused by mitochondrial uncoupling in SM are mediated by a metabolic rescue cycle involving Fgf21 as a protective myokine to prevent muscle wasting and linked to starvation-like response mechanisms. The results provide new insights into FGF21 function as a mediator of muscle induced regulation of whole body substrate metabolism and partitioning.