title: Phenotype selection reveals coevolution of muscle glycogen and protein and PTEN as a gate keeper for the accretion of muscle mass in adult female mice.
abstract: We have investigated molecular mechanisms for muscle mass accretion in a non-inbred mouse model (DU6P mice) characterized by extreme muscle mass. This extreme muscle mass was developed during 138 generations of phenotype selection for high protein content. Due to the repeated trait selection a complex setting of different mechanisms was expected to be enriched during the selection experiment. In muscle from 29-week female DU6P mice we have identified robust increases of protein kinase B activation (AKT, Ser-473, up to 2-fold) if compared to 11- and 54-week DU6P mice or controls. While a number of accepted effectors of AKT activation, including IGF-I, IGF-II, insulin/IGF-receptor, myostatin or integrin-linked kinase (ILK), were not correlated with this increase, phosphatase and tensin homologue deleted on chromosome 10 (PTEN) was down-regulated in 29-week female DU6P mice. In addition, higher levels of PTEN phosphorylation were found identifying a second mechanism of PTEN inhibition. Inhibition of PTEN and activation of AKT correlated with specific activation of p70S6 kinase and ribosomal protein S6, reduced phosphorylation of eukaryotic initiation factor 2α (eIF2α) and higher rates of protein synthesis in 29-week female DU6P mice. On the other hand, AKT activation also translated into specific inactivation of glycogen synthase kinase 3ß (GSK3ß) and an increase of muscular glycogen. In muscles from 29-week female DU6P mice a significant increase of protein/DNA was identified, which was not due to a reduction of protein breakdown or to specific increases of translation initiation. Instead our data support the conclusion that a higher rate of protein translation is contributing to the higher muscle mass in mid-aged female DU6P mice. Our results further reveal coevolution of high protein and high glycogen content during the selection experiment and identify PTEN as gate keeper for muscle mass in mid-aged female DU6P mice.
authors: Laboratory for Mouse Genetics, Research Unit Genetics & Biometry, Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany.
authors: Mandy
authors: M
authors: Sawitzky
authors: Anja
authors: A
authors: Zeissler
authors: Martina
authors: M
authors: Langhammer
authors: Maximilian
authors: M
authors: Bielohuby
authors: Peggy
authors: P
authors: Stock
authors: Harald M
authors: HM
authors: Hammon
authors: Solvig
authors: S
authors: Görs
authors: Cornelia C
authors: CC
authors: Metges
authors: Barbara J M
authors: BJ
authors: Stoehr
authors: Martin
authors: M
authors: Bidlingmaier
authors: Carolin
authors: C
authors: Fromm-Dornieden
authors: Bernhard G
authors: BG
authors: Baumgartner
authors: Bruno
authors: B
authors: Christ
authors: Bertram
authors: B
authors: Brenig
authors: Gerhard
authors: G
authors: Binder
authors: Friedrich
authors: F
authors: Metzger
authors: Ulla
authors: U
authors: Renne
authors: Andreas
authors: A
authors: Hoeflich
mesh_terms: D000818:Animals; D001835:Body Weight; D004789:Enzyme Activation; D019143:Evolution, Molecular; D005260:Female; D006003:Glycogen / Q000378:metabolism*; D007150:Immunohistochemistry; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009132:Muscles / Q000033:anatomy & histology* / Q000378:metabolism*; D009929:Organ Size; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D010641:Phenotype; D014176:Protein Biosynthesis; D059748:Proteolysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D013379:Substrate Specificity; D014020:Tissue Extracts
chemical_list: D014020:Tissue Extracts; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D006003:Glycogen; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse