Mitochondrial stress-induced metabolic adaptation of skeletal muscle - the role of GDF15 as a myokine

• Applicant: Professorin Dr. Susanne Klaus
• Subject Area: Nutritional Sciences ; Biochemistry
• Term: from 2017 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 336061747

We have established UCP1-tg mice with targeted ectopic expression of the mitochondrial uncoupling protein UCP1 in skeletal muscle as a model of healthy aging. Despite of a reduced muscle mass and strength these mice show a resistance to adverse metabolic effects of high fat diet feeding which is linked to a recruitment of brown adipocytes within white fat depots (browning). Skeletal muscle of this mouse model is characterized by a profound metabolic remodeling including the induction of cellular stress induced cytokines such as fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) as myokines. Using FGF21 ablated mice we could demonstrate that the browning of adipose tissue is due to the increased muscle FGF21 secretion but that FGF21 is dispensable for the beneficial metabolic effects and the reduced muscle mass. Because GDF15 overexpression induces a phenotype similar to UCP1-tg mice we now hypothesize that GDF15 could be, at least partially, responsible for these effects. GDF15 belongs to the transforming growth factor beta (TGFbeta) superfamily and its circulating levels are increased in several pathologies including cardiac disease and cancer. Therefore it is considered as a general marker of disease but so far little is known about specific cellular pathways and mechanism of action. Thus, it is not clear if it exerts overall beneficial or detrimental metabolic health effects. Although GDF15 has been linked to cachexia in general, there are only very few data on its direct effect on skeletal muscle. In this project we will explore the role of GDF15 for the metabolic phenotype of UCP1-tg mice and its specific effects on skeletal muscle metabolism in vivo and in vitro: (i) by examination of GDF15 ablated UCP1-tg mice, and (ii) by treatment of cultured murine and human myocytes with GDF15 in order to investigate direct effects on muscle and its cellular mode of action.

• DFG Programme: Research Grants