title: Myostatin propeptide mutation of the hypermuscularCompactmice decreases the formation of myostatin and improves insulin sensitivity.
abstract: The TGFβ family member myostatin (growth/differentiation factor-8) is a negative regulator of skeletal muscle growth. The hypermuscularCompactmice carry the 12-bpMstn(Cmpt-dl1Abc)deletion in the sequence encoding the propeptide region of the precursor promyostatin, and additional modifier genes of theCompactgenetic background contribute to determine the full expression of the phenotype. In this study, by using mice strains carrying mutant or wild-type myostatin alleles with theCompactgenetic background and nonmutant myostatin with the wild-type background, we studied separately the effect of theMstn(Cmpt-dl1Abc)mutation or theCompactgenetic background on morphology, metabolism, and signaling. We show that both theCompactmyostatin mutation andCompactgenetic background account for determination of skeletal muscle size. Despite the increased musculature ofCompacts, the absolute size of heart and kidney is not influenced by myostatin mutation; however, theCompactgenetic background increases them. BothCompactmyostatin and genetic background exhibit systemic metabolic effects. TheCompactmutation decreases adiposity and improves whole body glucose uptake, insulin sensitivity, and18FDG uptake of skeletal muscle and white adipose tissue, whereas theCompactgenetic background has the opposite effect. Importantly, the mutation does not prevent the formation of mature myostatin; however, a decrease in myostatin level was observed, leading to altered activation of Smad2, Smad1/5/8, and Akt, and an increased level of p-AS160, a Rab-GTPase-activating protein responsible for GLUT4 translocation. Based on our analysis, theCompactgenetic background strengthens the effect of myostatin mutation on muscle mass, but those can compensate for each other when systemic metabolic effects are compared.
authors.affiliation: Department of Biochemistry, Faculty of Medicine, University of Szeged, Szeged, Hungary.
authors.forename: Tamas
authors.initials: T
authors.lastname: Kocsis
authors.affiliation: Scanomed, Debrecen, Hungary.
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Trencsenyi
authors.affiliation: Department of Biochemistry, Faculty of Medicine, University of Szeged, Szeged, Hungary.
authors.forename: Kitti
authors.initials: K
authors.lastname: Szabo
authors.affiliation: Department of Biochemistry, Faculty of Medicine, University of Szeged, Szeged, Hungary.
authors.forename: Julia Aliz
authors.initials: JA
authors.lastname: Baan
authors.affiliation: Department of Biochemistry, Faculty of Medicine, University of Szeged, Szeged, Hungary.
authors.forename: Geza
authors.initials: G
authors.lastname: Muller
authors.affiliation: Department of Biochemistry, Faculty of Medicine, University of Szeged, Szeged, Hungary.
authors.forename: Luca
authors.initials: L
authors.lastname: Mendler
authors.affiliation: Scanomed, Debrecen, Hungary.
authors.forename: Ildiko
authors.initials: I
authors.lastname: Garai
authors.affiliation: INSTAND, Dusseldorf, Germany; and.
authors.forename: Hans
authors.initials: H
authors.lastname: Reinauer
authors.affiliation: Institute of Genetics, Biological Research Centre, Hungarian Academy of Sciences, Szeged, Hungary.
authors.forename: Ferenc
authors.initials: F
authors.lastname: Deak
authors.affiliation: Department of Biochemistry, Faculty of Medicine, University of Szeged, Szeged, Hungary.
authors.forename: Laszlo
authors.initials: L
authors.lastname: Dux
authors.affiliation: Department of Biochemistry, Faculty of Medicine, University of Szeged, Szeged, Hungary; keller.aniko@med.u-szeged.hu.
authors.forename: Aniko
authors.initials: A
authors.lastname: Keller-Pinter
mesh_terms: D052436:Adipose Tissue, White / Q000000981:diagnostic imaging / Q000378:metabolism*; D050154:Adiposity / Q000235:genetics*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D019788:Fluorodeoxyglucose F18; D020690:GTPase-Activating Proteins / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006321:Heart / Q000033:anatomy & histology / Q000000981:diagnostic imaging; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D007668:Kidney / Q000033:anatomy & histology / Q000000981:diagnostic imaging; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D064847:Multimodal Imaging; D018482:Muscle, Skeletal / Q000000981:diagnostic imaging / Q000254:growth & development / Q000378:metabolism*; D009154:Mutation; D055435:Myostatin / Q000235:genetics*; D009929:Organ Size / Q000235:genetics; D010750:Phosphoproteins; D049268:Positron-Emission Tomography; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019275:Radiopharmaceuticals; D051898:Smad1 Protein / Q000378:metabolism; D051899:Smad2 Protein / Q000378:metabolism; D051902:Smad5 Protein / Q000378:metabolism; D051904:Smad8 Protein / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D020690:GTPase-Activating Proteins; D007328:Insulin; C525912:Mstn protein, mouse; D055435:Myostatin; D010750:Phosphoproteins; D019275:Radiopharmaceuticals; D051898:Smad1 Protein; C497401:Smad1 protein, mouse; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051902:Smad5 Protein; C497798:Smad5 protein, mouse; D051904:Smad8 Protein; C491621:Smad9 protein, mouse; C505647:Tbc1d4 protein, mouse; D019788:Fluorodeoxyglucose F18; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose
keywords: 2-deoxy-2-[18F]fluoro-d-glucose; Compact mice; insulin resistance; myostatin; skeletal muscle