TY - JOUR A1 - Wei, Xiaoyan A1 - Franke, Julia A1 - Ost, Mario A1 - Wardelmann, Kristina A1 - Börno, Stefan A1 - Timmermann, Bernd A1 - Meierhofer, David A1 - Kleinridders, Andre A1 - Klaus, Susanne A1 - Stricker, Sigmar T1 - Cell autonomous requirement of neurofibromin (Nf1) for postnatal muscle hypertrophic growth and metabolic homeostasis JF - Journal of cachexia, sarcopenia and muscle N2 - 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. KW - neurofibromatosis KW - NF1 KW - myopathy KW - muscle atrophy KW - muscle metabolism KW - muscle fibre type KW - AMPK Y1 - 2020 U6 - https://doi.org/10.1002/jcsm.12632 SN - 2190-5991 SN - 2190-6009 VL - 11 IS - 6 SP - 1758 EP - 1778 PB - Wiley CY - Hoboken ER - TY - JOUR A1 - Franz, Kristina A1 - Ost, Mario A1 - Otten, Lindsey A1 - Herpich, Catrin A1 - Coleman, Verena A1 - Endres, Anne-Sophie A1 - Klaus, Susanne A1 - Müller-Werdan, Ursula A1 - Norman, Kristina T1 - Higher serum levels of fibroblast growth factor 21 in old patients with cachexia JF - Nutrition : the international journal of applied and basic nutritional sciences N2 - 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. KW - Fibroblast growth factor 21 KW - Cachexia KW - Anorexia KW - Aging KW - Biomarker Y1 - 2018 U6 - https://doi.org/10.1016/j.nut.2018.11.004 SN - 0899-9007 SN - 1873-1244 VL - 63-64 SP - 81 EP - 86 PB - Elsevier CY - New York ER - TY - JOUR A1 - Fernando, Raquel A1 - Drescher, Cathleen A1 - Deubel, Stefanie A1 - Jung, Tobias A1 - Ost, Mario A1 - Klaus, Susanne A1 - Grune, Tilman A1 - Castro, Jose Pedro T1 - Low proteasomal activity in fast skeletal muscle fibers is not associated with increased age-related oxidative damage JF - Experimental gerontology N2 - 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. KW - Proteasomal system KW - Skeletal muscle KW - Fast and slow fibers KW - Polyubiquitination KW - Oxidized proteins KW - Antioxidants KW - Aging KW - Mitochondrial respiration Y1 - 2018 U6 - https://doi.org/10.1016/j.exger.2018.10.018 SN - 0531-5565 SN - 1873-6815 VL - 117 SP - 45 EP - 52 PB - Elsevier CY - Oxford ER - TY - JOUR A1 - Ost, Mario A1 - Igual Gil, Carla A1 - Coleman, Verena A1 - Keipert, Susanne A1 - Efstathiou, Sotirios A1 - Vidic, Veronika A1 - Weyers, Miriam A1 - Klaus, Susanne T1 - Muscle-derived GDF15 drives diurnal anorexia and systemic metabolic remodeling during mitochondrial stress JF - EMBO reports N2 - 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. KW - anorexia KW - GDF15 KW - integrated stress response KW - mitochondrial dysfunction KW - muscle wasting Y1 - 2020 U6 - https://doi.org/10.15252/embr.201948804 SN - 1469-221X SN - 1469-3178 VL - 21 IS - 3 PB - Wiley CY - Hoboken ER - TY - JOUR A1 - Klaus, Susanne A1 - Igual Gil, Carla A1 - Ost, Mario T1 - Regulation of diurnal energy balance by mitokines JF - Cellular and molecular life sciences : CMLS N2 - 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. KW - Mitochondria KW - FGF21 KW - GDF15 KW - Circadian rhythm KW - Hormones KW - Nutrition Y1 - 2021 U6 - https://doi.org/10.1007/s00018-020-03748-9 SN - 1420-682X SN - 1420-9071 VL - 78 IS - 7 SP - 3369 EP - 3384 PB - Springer International Publishing AG CY - Cham (ZG) ER - TY - JOUR A1 - Igual Gil, Carla A1 - Ost, Mario A1 - Kasch, Juliane A1 - Schumann, Sara A1 - Heider, Sarah A1 - Klaus, Susanne T1 - Role of GDF15 in active lifestyle induced metabolic adaptations and acute exercise response in mice JF - Scientific reports N2 - 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. Y1 - 2019 U6 - https://doi.org/10.1038/s41598-019-56922-w SN - 2045-2322 VL - 9 PB - Nature Publ. Group CY - London ER -