Mitochondrial stress-induced metabolic adaptation of skeletal muscle - the role of GDF15 as a myokine
Biochemistry
Final Report Abstract
Growth differentiation factor (GDF15) is released from various tissues in response to cellular stress and increased circulating levels are observed in numerous disorders including mitochondrial diseases. The best described metabolic action of GDF15 is the suppression of food intake observed after overexpression or pharmacological application. This is dependent on GFRAL (GDNF receptor alpha-like) the unique receptor for GDF15 signaling uniquely expressed in the hind brain. We identified GDF15 as a myokine induced by mitochondrial dysfunction in the UCP1-tg mouse model which has a skeletal muscle-specific overexpression of uncoupling protein 1 (UCP1) leading to an impaired muscle oxidative phosphorylation capacity. Despite a decreased muscle mass and strength linked to a remodeling of skeletal muscle metabolism, these mice display a healthy metabolic phenotype and obesity resistance. The objectives/ questions addressed in of this project were two-fold: (1) To what extent is GDF15 secretion from skeletal muscle responsible for the phenotypical and metabolic features of UCP1-tg mice? (2) What are the autocrine (cell-autonomous) effects of GDF15 on skeletal muscle metabolic function? With regard to the first objective, we could show that GDF15 as a stress induced myokine is dispensable for muscle wasting and remodeling during mitochondrial stress in UCP1-tg mice. However, GDF15 proved responsible for the metabolic adaptations observed in the UCP1-tg mouse model such as the increased metabolic flexibility, browning of white adipose tissue (WAT), and improved insulin sensitivity, highlighting the metabolic role of GDF15 as a myomitokine. Importantly, we could demonstrate for the first time an endocrine crosstalk via endogenous GDF15 that promotes a diurnal (day time restricted) anorectic response which controls the systemic metabolic adaptation. Regarding the second objective, we did not find evidence for a direct (auto- or paracrine) nor indirect effect of muscle derived GDF15 on the muscle phenotype of UCP1-tg mice. However, using exhaustive exercise as a different type of muscle stress we obtained indirect evidence that local GDF15 expression might play a role in mitigating the cellular exercise stress response. In further studies we intend to investigated in more detail the metabolic and pathophysiological significance of the GDF15-GFRAL axis, focusing on its role in appetite and stress related behavior.
Publications
- (2019) Role of GDF15 in active lifestyle induced metabolic adaptations and acute exercise response in mice. Sci Rep. 9(1):20120
Igual Gil C, Ost M, Kasch J, Schumann S, Heider S, Klaus S
(See online at https://doi.org/10.1038/s41598-019-56922-w) - (2020) GDF15 governs a diurnal anorexia and systemic metabolic response during muscle mitochondrial stress. EMBO Rep. 21(3):e48804
Ost M, Igual Gil C, Coleman V, Keipert S, Efstathiou S, Vidic V, Weyers M, Klaus S
(See online at https://doi.org/10.15252/embr.201948804) - (2020) Mitochondrial uncoupling and longevity – a role for mitokines? Exp Geront. 130:110796
Klaus S, Ost M
(See online at https://doi.org/10.1016/j.exger.2019.110796) - (2021) Regulation of diurnal energy balance by mitokines. Cell Mol Life Sci. 78(7):3369-3384
Klaus S, Igual Gil C, Ost M
(See online at https://doi.org/10.1007/s00018-020-03748-9)
