The role of fibroblast growth factor 21 in mediating altered metabolism of the Deletor mouse model for mitochondrial myopathy

This study investigates the metabolic consequences of a biomarker for mitochondrial myopathies, using the mouse as a model organism. The studied biomarker is fibroblast growth factor 21 (FGF21), which is secreted in high amounts from the diseased muscle tissue. It is an endocrine hormone that regulates lipid metabolism, and in healthy individuals it is mainly secreted from the liver. I utilized skeletal muscle samples from mice that were either wild type or had a mitochondrial myopathy, both with or without a whole-body knockout of FGF21. I analysed a data set from a targeted metabolomic experiment conducted on the skeletal muscle samples. The experiment was performed by our collaborator Vidya Velagapudi. Additionally I measured protein and mRNA expression of selected enzymes from the muscle samples. This study shows, that the cytokine FGF21 contributes to the disease progression of mitochondrial myopathy. The aspects of pathophysiology it regulates were all found to center on the metabolic pathway of one carbon (1C) metabolism. Serine de novo synthesis shuttles glucose carbons into 1C metabolism. The transsulfuration pathway produces glutathione using carbon units from the 1C pathway. The results of this study show, that FGF21 mediates the upregulation of alternative carbon donors in one carbon metabolism, especially serine biosynthesis, and the elevated utilisation of carbon units in the transsulfuration pathway. Not all of the metabolic changes characteristic of mitochondrial myopathy were affected by FGF21, e.g. the upregulation of acyl carnitines seen in mitochondrial myopathy was not affected by the knock-out of FGF21

Fibroblast Growth Factor 21 Drives Dynamics of Local and Systemic Stress Responses in Mitochondrial Myopathy with mtDNA Deletions

AbstractMitochondrial dysfunction elicits stress responses that safeguard cellular homeostasis against metabolic insults. Mitochondrial integrated stress response (ISRmt) is a major response to mitochondrial (mt)DNA expression stress (mtDNA maintenance, translation defects), but the knowledge of dynamics or interdependence of components is lacking. We report that in mitochondrial myopathy, ISRmt progresses in temporal stages and development from early to chronic and is regulated by autocrine and endocrine effects of FGF21, a metabolic hormone with pleiotropic effects. Initial disease signs induce transcriptional ISRmt (ATF5, mitochondrial one-carbon cycle, FGF21, and GDF15). The local progression to 2nd metabolic ISRmt stage (ATF3, ATF4, glucose uptake, serine biosynthesis, and transsulfuration) is FGF21 dependent. Mitochondrial unfolded protein response marks the 3rd ISRmt stage of failing tissue. Systemically, FGF21 drives weight loss and glucose preference, and modifies metabolism and respiratory chain deficiency in a specific hippocampal brain region. Our evidence indicates that FGF21 is a local and systemic messenger of mtDNA stress in mice and humans with mitochondrial disease.</div

Fibroblast Growth Factor 21 Drives Dynamics of Local and Systemic Stress Responses in Mitochondrial Myopathy with mtDNA Deletions

Mitochondrial dysfunction elicits stress responses that safeguard cellular homeostasis against metabolic insults. Mitochondrial integrated stress response (ISRmt) is a major response to mitochondrial (mt)DNA expression stress (mtDNA maintenance, translation defects), but the knowledge of dynamics or interdependence of components is lacking. We report that in mitochondrial myopathy, ISRmt progresses in temporal stages and development from early to chronic and is regulated by autocrine and endocrine effects of FGF21, a metabolic hormone with pleiotropic effects. Initial disease signs induce transcriptional ISRmt (ATF5, mitochondria) one-carbon cycle, FGF21, and GDF15). The local progression to 2nd metabolic ISRmt stage (ATF3, ATF4, glucose uptake, serine biosynthesis, and transsulfuration) is FGF21 dependent. Mitochondria! unfolded protein response marks the 3rd ISRmt stage of failing tissue. Systemically, FGF21 drives weight loss and glucose preference, and modifies metabolism and respiratory chain deficiency in a specific hippocampal brain region. Our evidence indicates that FGF21 is a local and systemic messenger of mtDNA stress in mice and humans with mitochondrial disease.Peer reviewe