@article{FranzOstOttenetal.2018,
  author    = {Franz, Kristina and Ost, Mario and Otten, Lindsey and Herpich, Catrin and Coleman, Verena and Endres, Anne-Sophie and Klaus, Susanne and M{\"u}ller-Werdan, Ursula and Norman, Kristina},
  title     = {Higher serum levels of fibroblast growth factor 21 in old patients with cachexia},
  series = {Nutrition : the international journal of applied and basic nutritional sciences},
  volume    = {63-64},
  journal   = {Nutrition : the international journal of applied and basic nutritional sciences},
  publisher = {Elsevier},
  address   = {New York},
  issn      = {0899-9007},
  doi       = {10.1016/j.nut.2018.11.004},
  pages     = {81 -- 86},
  year      = {2018},
  abstract  = {Objective: Fibroblast growth factor (FGF)21 is promptly induced by short fasting in animal models to regulate glucose and fat metabolism. Data on FGF21 in humans are inconsistent and FGF21 has not yet been investigated in old patients with cachexia, a complex syndrome characterized by inflammation and weight loss. The aim of this study was to explore the association of FGF21 with cachexia in old patients compared with their healthy counterparts. Methods: Serum FGF21 and its inactivating enzyme fibroblast activation protein (FAP)-cc were measured with enzyme-linked immunoassays. Cachexia was defined as >= 5\% weight loss in the previous 3 mo and concurrent anorexia (Council on Nutrition appetite questionnaire). Results: We included 103 patients with and without cachexia (76.9 +/- 5.2 y of age) and 56 healthy controls (72.9 +/- 5.9 y of age). Cachexia was present in 16.5\% of patients. These patients had significantly higher total FGF21 levels than controls (952.1 +/- 821.3 versus 525.2 +/- 560.3 pg/mL; P= 0.012) and the lowest FGF21 levels (293.3 +/- 150.9 pg/mL) were found in the control group (global P < 0.001). Although FAP-alpha did not differ between the three groups (global P = 0.082), bioactive FGF21 was significantly higher in patients with cachexia (global P = 0.002). Risk factor-adjusted regression analyses revealed a significant association between cachexia and total ((beta = 649.745 pg/mL; P < 0.001) and bioactive FGF21 (beta = 393.200 pg/mL; P <0.001), independent of sex, age, and body mass index. Conclusions: Patients with cachexia exhibited the highest FGF21 levels. Clarification is needed to determine whether this is an adaptive response to nutrient deprivation in disease-related cachexia or whether the increased FGF21 values contribute to the catabolic state. (C) 2018 Elsevier Inc. All rights reserved.},
  language  = {en}
}
@article{WeiFrankeOstetal.2020,
  author    = {Wei, Xiaoyan and Franke, Julia and Ost, Mario and Wardelmann, Kristina and B{\"o}rno, Stefan and Timmermann, Bernd and Meierhofer, David and Kleinridders, Andre and Klaus, Susanne and Stricker, Sigmar},
  title     = {Cell autonomous requirement of neurofibromin (Nf1) for postnatal muscle hypertrophic growth and metabolic homeostasis},
  series = {Journal of cachexia, sarcopenia and muscle},
  volume    = {11},
  journal   = {Journal of cachexia, sarcopenia and muscle},
  number    = {6},
  publisher = {Wiley},
  address   = {Hoboken},
  issn      = {2190-5991},
  doi       = {10.1002/jcsm.12632},
  pages     = {1758 -- 1778},
  year      = {2020},
  abstract  = {Background Neurofibromatosis type 1 (NF1) is a multi-organ disease caused by mutations in neurofibromin 1 (NF1). Amongst other features, NF1 patients frequently show reduced muscle mass and strength, impairing patients' mobility and increasing the risk of fall. The role of Nf1 in muscle and the cause for the NF1-associated myopathy are mostly unknown. Methods To dissect the function ofNf1in muscle, we created muscle-specific knockout mouse models for NF1, inactivatingNf1in the prenatal myogenic lineage either under the Lbx1 promoter or under the Myf5 promoter. Mice were analysed during prenatal and postnatal myogenesis and muscle growth. Results Nf1(Lbx1)and Nf1(Myf5)animals showed only mild defects in prenatal myogenesis. Nf1(Lbx1)animals were perinatally lethal, while Nf1(Myf5)animals survived only up to approximately 25 weeks. A comprehensive phenotypic characterization of Nf1(Myf5)animals showed decreased postnatal growth, reduced muscle size, and fast fibre atrophy. Proteome and transcriptome analyses of muscle tissue indicated decreased protein synthesis and increased proteasomal degradation, and decreased glycolytic and increased oxidative activity in muscle tissue. High-resolution respirometry confirmed enhanced oxidative metabolism in Nf1(Myf5)muscles, which was concomitant to a fibre type shift from type 2B to type 2A and type 1. Moreover, Nf1(Myf5)muscles showed hallmarks of decreased activation of mTORC1 and increased expression of atrogenes. Remarkably, loss of Nf1 promoted a robust activation of AMPK with a gene expression profile indicative of increased fatty acid catabolism. Additionally, we observed a strong induction of genes encoding catabolic cytokines in muscle Nf1(Myf5)animals, in line with a drastic reduction of white, but not brown adipose tissue. Conclusions Our results demonstrate a cell autonomous role for Nf1 in myogenic cells during postnatal muscle growth required for metabolic and proteostatic homeostasis. Furthermore, Nf1 deficiency in muscle drives cross-tissue communication and mobilization of lipid reserves.},
  language  = {en}
}
@misc{KlausOst2020,
  author    = {Klaus, Susanne and Ost, Mario},
  title     = {Mitochondrial uncoupling and longevity},
  series = {Experimental gerontology},
  volume    = {130},
  journal   = {Experimental gerontology},
  publisher = {Elsevier Science},
  address   = {Amsterdam},
  issn      = {0531-5565},
  doi       = {10.1016/j.exger.2019.110796},
  year      = {2020},
  abstract  = {Aging has been viewed both as a random process due to accumulation of molecular and cellular damage over time and as a programmed process linked to cellular pathway important for growth and maturation. These views converge on mitochondria as both the major producer of damaging reactive oxidant species (ROS) and as signaling organelles. A finite proton leak across the inner mitochondrial membrane leading to a slight uncoupling of oxidative phosphorylation and respiration is an intrinsic property of all mitochondria and according to the "uncoupling to survive" hypothesis it has evolved to protect against ROS production to minimize oxidative damage. This hypothesis is supported by evidence linking an increased endogenous, uncoupling protein (UCP1) mediated, as well as experimentally induced mitochondrial uncoupling to an increased lifespan in rodents. This is possibly due to the synergistic activation of molecular pathways linked to life extending effects of caloric restriction as well as a mitohormetic response. Mitohormesis is an adaptive stress response through mitonuclear signaling which increases stress resistance resulting in health promoting effects. Part of this response is the induction of fibroblast growth factor 21 (FGF21) and growth and differentiation factor 15 (GDF15), two stress-induced mitokines which elicit beneficial systemic metabolic effects via endocrine action.},
  language  = {en}
}
@misc{IgualGilOstKaschetal.2019,
  author    = {Igual Gil, Carla and Ost, Mario and Kasch, Juliane and Schumann, Sara and Heider, Sarah and Klaus, Susanne},
  title     = {Role of GDF15 in active lifestyle induced metabolic adaptations and acute exercise response in mice},
  series = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe},
  journal   = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe},
  number    = {1090},
  issn      = {1866-8372},
  doi       = {10.25932/publishup-46054},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-460541},
  pages     = {11},
  year      = {2019},
  abstract  = {Physical activity is an important contributor to muscle adaptation and metabolic health. Growth differentiation factor 15 (GDF15) is established as cellular and nutritional stress-induced cytokine but its physiological role in response to active lifestyle or acute exercise is unknown. Here, we investigated the metabolic phenotype and circulating GDF15 levels in lean and obese male C57BI/6J mice with long-term voluntary wheel running (VWR) intervention. Additionally, treadmill running capacity and exercise-induced muscle gene expression was examined in GDF15-ablated mice. Active lifestyle mimic via VWR improved treadmill running performance and, in obese mice, also metabolic phenotype. The post-exercise induction of skeletal muscle transcriptional stress markers was reduced by VWR. Skeletal muscle GDF15 gene expression was very low and only transiently increased post-exercise in sedentary but not in active mice. Plasma GDF15 levels were only marginally affected by chronic or acute exercise. In obese mice, VWR reduced GDF15 gene expression in different tissues but did not reverse elevated plasma GDF15. Genetic ablation of GDF15 had no effect on exercise performance but augmented the post exercise expression of transcriptional exercise stress markers (Atf3, Atf6, and Xbp1s) in skeletal muscle. We conclude that skeletal muscle does not contribute to circulating GDF15 in mice, but muscle GDF15 might play a protective role in the exercise stress response.},
  language  = {en}
}
@article{OstIgualGilColemanetal.2020,
  author    = {Ost, Mario and Igual Gil, Carla and Coleman, Verena and Keipert, Susanne and Efstathiou, Sotirios and Vidic, Veronika and Weyers, Miriam and Klaus, Susanne},
  title     = {Muscle-derived GDF15 drives diurnal anorexia and systemic metabolic remodeling during mitochondrial stress},
  series = {EMBO reports},
  volume    = {21},
  journal   = {EMBO reports},
  number    = {3},
  publisher = {Wiley},
  address   = {Hoboken},
  issn      = {1469-221X},
  doi       = {10.15252/embr.201948804},
  pages     = {14},
  year      = {2020},
  abstract  = {Mitochondrial dysfunction promotes metabolic stress responses in a cell-autonomous as well as organismal manner. The wasting hormone growth differentiation factor 15 (GDF15) is recognized as a biomarker of mitochondrial disorders, but its pathophysiological function remains elusive. To test the hypothesis that GDF15 is fundamental to the metabolic stress response during mitochondrial dysfunction, we investigated transgenic mice (Ucp1-TG) with compromised muscle-specific mitochondrial OXPHOS capacity via respiratory uncoupling. Ucp1-TG mice show a skeletal muscle-specific induction and diurnal variation of GDF15 as a myokine. Remarkably, genetic loss of GDF15 in Ucp1-TG mice does not affect muscle wasting or transcriptional cell-autonomous stress response but promotes a progressive increase in body fat mass. Furthermore, muscle mitochondrial stress-induced systemic metabolic flexibility, insulin sensitivity, and white adipose tissue browning are fully abolished in the absence of GDF15. Mechanistically, we uncovered a GDF15-dependent daytime-restricted anorexia, whereas GDF15 is unable to suppress food intake at night. Altogether, our evidence suggests a novel diurnal action and key pathophysiological role of mitochondrial stress-induced GDF15 in the regulation of systemic energy metabolism.},
  language  = {en}
}
@article{IgualGilOstKaschetal.2019,
  author    = {Igual Gil, Carla and Ost, Mario and Kasch, Juliane and Schumann, Sara and Heider, Sarah and Klaus, Susanne},
  title     = {Role of GDF15 in active lifestyle induced metabolic adaptations and acute exercise response in mice},
  series = {Scientific reports},
  volume    = {9},
  journal   = {Scientific reports},
  publisher = {Nature Publ. Group},
  address   = {London},
  issn      = {2045-2322},
  doi       = {10.1038/s41598-019-56922-w},
  pages     = {9},
  year      = {2019},
  abstract  = {Physical activity is an important contributor to muscle adaptation and metabolic health. Growth differentiation factor 15 (GDF15) is established as cellular and nutritional stress-induced cytokine but its physiological role in response to active lifestyle or acute exercise is unknown. Here, we investigated the metabolic phenotype and circulating GDF15 levels in lean and obese male C57BI/6J mice with long-term voluntary wheel running (VWR) intervention. Additionally, treadmill running capacity and exercise-induced muscle gene expression was examined in GDF15-ablated mice. Active lifestyle mimic via VWR improved treadmill running performance and, in obese mice, also metabolic phenotype. The post-exercise induction of skeletal muscle transcriptional stress markers was reduced by VWR. Skeletal muscle GDF15 gene expression was very low and only transiently increased post-exercise in sedentary but not in active mice. Plasma GDF15 levels were only marginally affected by chronic or acute exercise. In obese mice, VWR reduced GDF15 gene expression in different tissues but did not reverse elevated plasma GDF15. Genetic ablation of GDF15 had no effect on exercise performance but augmented the post exercise expression of transcriptional exercise stress markers (Atf3, Atf6, and Xbp1s) in skeletal muscle. We conclude that skeletal muscle does not contribute to circulating GDF15 in mice, but muscle GDF15 might play a protective role in the exercise stress response.},
  language  = {en}
}
@article{KlausIgualGilOst2021,
  author    = {Klaus, Susanne and Igual Gil, Carla and Ost, Mario},
  title     = {Regulation of diurnal energy balance by mitokines},
  series = {Cellular and molecular life sciences : CMLS},
  volume    = {78},
  journal   = {Cellular and molecular life sciences : CMLS},
  number    = {7},
  publisher = {Springer International Publishing AG},
  address   = {Cham (ZG)},
  issn      = {1420-682X},
  doi       = {10.1007/s00018-020-03748-9},
  pages     = {3369 -- 3384},
  year      = {2021},
  abstract  = {The mammalian system of energy balance regulation is intrinsically rhythmic with diurnal oscillations of behavioral and metabolic traits according to the 24 h day/night cycle, driven by cellular circadian clocks and synchronized by environmental or internal cues such as metabolites and hormones associated with feeding rhythms. Mitochondria are crucial organelles for cellular energy generation and their biology is largely under the control of the circadian system. Whether mitochondrial status might also feed-back on the circadian system, possibly via mitokines that are induced by mitochondrial stress as endocrine-acting molecules, remains poorly understood. Here, we describe our current understanding of the diurnal regulation of systemic energy balance, with focus on fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15), two well-known endocrine-acting metabolic mediators. FGF21 shows a diurnal oscillation and directly affects the output of the brain master clock. Moreover, recent data demonstrated that mitochondrial stress-induced GDF15 promotes a day-time restricted anorexia and systemic metabolic remodeling as shown in UCP1-transgenic mice, where both FGF21 and GDF15 are induced as myomitokines. In this mouse model of slightly uncoupled skeletal muscle mitochondria GDF15 proved responsible for an increased metabolic flexibility and a number of beneficial metabolic adaptations. However, the molecular mechanisms underlying energy balance regulation by mitokines are just starting to emerge, and more data on diurnal patterns in mouse and man are required. This will open new perspectives into the diurnal nature of mitokines and action both in health and disease.},
  language  = {en}
}
@article{FernandoDrescherDeubeletal.2018,
  author    = {Fernando, Raquel and Drescher, Cathleen and Deubel, Stefanie and Jung, Tobias and Ost, Mario and Klaus, Susanne and Grune, Tilman and Castro, Jose Pedro},
  title     = {Low proteasomal activity in fast skeletal muscle fibers is not associated with increased age-related oxidative damage},
  series = {Experimental gerontology},
  volume    = {117},
  journal   = {Experimental gerontology},
  publisher = {Elsevier},
  address   = {Oxford},
  issn      = {0531-5565},
  doi       = {10.1016/j.exger.2018.10.018},
  pages     = {45 -- 52},
  year      = {2018},
  abstract  = {The skeletal muscle is a crucial tissue for maintaining whole body homeostasis. Aging seems to have a disruptive effect on skeletal muscle homeostasis including proteostasis. However, how aging specifically impacts slow and fast twitch fiber types remains elusive. Muscle proteostasis is largely maintained by the proteasomal system. Here we characterized the proteasomal system in two different fiber types, using a non-sarcopenic aging model. By analyzing the proteasomal activity and amount, as well as the polyubiquitinated proteins and the level of protein oxidation in Musculus soleus (Sol) and Musculus extensor digitorum longus (EDL), we found that the slow twitch Sol muscle shows an overall higher respiratory and proteasomal activity in young and old animals. However, especially during aging the fast twitch EDL muscle reduces protein oxidation by an increase of antioxidant capacity. Thus, under adaptive non-sarcopenic conditions, the two fibers types seem to have different strategies to avoid age-related changes.},
  language  = {en}
}