@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}
}
@article{CuiSchlesingerSchoenhalsetal.2016,
  author    = {Cui, Huanhuan and Schlesinger, Jenny and Schoenhals, Sophia and Toenjes, Martje and Dunkel, Ilona and Meierhofer, David and Cano, Elena and Schulz, Kerstin and Berger, Michael F. and Haack, Timm and Abdelilah-Seyfried, Salim and Bulyk, Martha L. and Sauer, Sascha and Sperling, Silke R.},
  title     = {Phosphorylation of the chromatin remodeling factor DPF3a induces cardiac hypertrophy through releasing HEY repressors from DNA},
  series = {Nucleic acids research},
  volume    = {44},
  journal   = {Nucleic acids research},
  publisher = {Oxford Univ. Press},
  address   = {Oxford},
  issn      = {0305-1048},
  doi       = {10.1093/nar/gkv1244},
  pages     = {2538 -- 2553},
  year      = {2016},
  abstract  = {DPF3 (BAF45c) is a member of the BAF chromatin remodeling complex. Two isoforms have been described, namely DPF3a and DPF3b. The latter binds to acetylated and methylated lysine residues of histones. Here, we elaborate on the role of DPF3a and describe a novel pathway of cardiac gene transcription leading to pathological cardiac hypertrophy. Upon hypertrophic stimuli, casein kinase 2 phosphorylates DPF3a at serine 348. This initiates the interaction of DPF3a with the transcriptional repressors HEY, followed by the release of HEY from the DNA. Moreover, BRG1 is bound by DPF3a, and is thus recruited to HEY genomic targets upon interaction of the two components. Consequently, the transcription of downstream targets such as NPPA and GATA4 is initiated and pathological cardiac hypertrophy is established. In human, DPF3a is significantly up-regulated in hypertrophic hearts of patients with hypertrophic cardiomyopathy or aortic stenosis. Taken together, we show that activation of DPF3a upon hypertrophic stimuli switches cardiac fetal gene expression from being silenced by HEY to being activated by BRG1. Thus, we present a novel pathway for pathological cardiac hypertrophy, whose inhibition is a long-term therapeutic goal for the treatment of the course of heart failure.},
  language  = {en}
}