Myostatin propeptide mutation of the hypermuscular Compact mice decreases the formation of myostatin and improves insulin sensitivity

被引:13
作者
Kocsis, Tamas [1 ]
Trencsenyi, Gyorgy [2 ]
Szabo, Kitti [1 ]
Baan, Julia Aliz [1 ]
Muller, Geza [1 ]
Mendler, Luca [1 ]
Garai, Ildiko [2 ]
Reinauer, Hans [3 ]
Deak, Ferenc [4 ]
Dux, Laszlo [1 ]
Keller-Pinter, Aniko [1 ]
机构
[1] Univ Szeged, Dept Biochem, Fac Med, Dom Sq 9, H-6720 Szeged, Hungary
[2] Scanomed, Debrecen, Hungary
[3] INSTAND, Dusseldorf, Germany
[4] Hungarian Acad Sci, Inst Genet, Biol Res Ctr, Szeged, Hungary
来源
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM | 2017年 / 312卷 / 03期
关键词
myostatin; Compact mice; skeletal muscle; insulin resistance; 2-deoxy-2-[F-18] fluoro-D-glucose; SKELETAL-MUSCLE MASS; LIVER-REGENERATION; FAT ACCUMULATION; PROTEIN AXIS; MOUSE LINE; GROWTH; GENE; EXPRESSION; MUSCULARITY; INCREASES;
D O I
10.1152/ajpendo.00216.2016
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The TGF beta family member myostatin (growth/differentiation factor-8) is a negative regulator of skeletal muscle growth. The hypermuscular Compact mice carry the 12-bp Mstn(Cmpt-dl1Abc) deletion in the sequence encoding the propeptide region of the precursor promyostatin, and additional modifier genes of the Compact genetic 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 the Compact genetic background and nonmutant myostatin with the wild-type background, we studied separately the effect of the Mstn(Cmpt-dl1Abc) mutation or the Compact genetic background on morphology, metabolism, and signaling. We show that both the Compact myostatin mutation and Compact genetic background account for determination of skeletal muscle size. Despite the increased musculature of Compacts, the absolute size of heart and kidney is not influenced by myostatin mutation; however, the Compact genetic background increases them. Both Compact myostatin and genetic background exhibit systemic metabolic effects. The Compact mutation decreases adiposity and improves whole body glucose uptake, insulin sensitivity, and (18)FDG uptake of skeletal muscle and white adipose tissue, whereas the Compact genetic 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, the Compact genetic background strengthens the effect of myostatin mutation on muscle mass, but those can compensate for each other when systemic metabolic effects are compared.
引用
收藏
页码:E150 / E160
页数:11
相关论文
共 57 条
[1]   Lack of myostatin results in excessive muscle growth but impaired force generation [J].
Amthor, Helge ;
Macharia, Raymond ;
Navarrete, Roberto ;
Schuelke, Markus ;
Brown, Susan C. ;
Otto, Anthony ;
Voit, Thomas ;
Muntoni, Francesco ;
Vrbova, Gerta ;
Partridge, Terence ;
Zammit, Peter ;
Bunger, Lutz ;
Patel, Ketan .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2007, 104 (06) :1835-1840
[2]   Standard operating procedures for describing and performing metabolic tests of glucose homeostasis in mice [J].
Ayala, Julio E. ;
Samuel, Varman T. ;
Morton, Gregory J. ;
Obici, Silvana ;
Croniger, Colleen M. ;
Shulman, Gerald I. ;
Wasserman, David H. ;
McGuinness, Owen P. .
DISEASE MODELS & MECHANISMS, 2010, 3 (9-10) :525-534
[3]   The Compact Mutation of Myostatin Causes a Glycolytic Shift in the Phenotype of Fast Skeletal Muscles [J].
Baan, Julia Aliz ;
Kocsis, Tamas ;
Keller-Pinter, Aniko ;
Muller, Geza ;
Zador, Erno ;
Dux, Laszlo ;
Mendler, Luca .
JOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY, 2013, 61 (12) :889-900
[4]   Single cysteine to tyrosine transition inactivates the growth inhibitory function of Piedmontese myostatin [J].
Berry, C ;
Thomas, M ;
Langley, B ;
Sharma, M ;
Kambadur, R .
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY, 2002, 283 (01) :C135-C141
[5]   Hypermuscular mice with mutation in the myostatin gene display altered calcium signalling [J].
Bodnar, Dora ;
Geyer, Nikolett ;
Ruzsnavszky, Olga ;
Olah, Tamas ;
Hegyi, Bence ;
Sztretye, Monika ;
Fodor, Janos ;
Dienes, Beatrix ;
Balogh, Agnes ;
Papp, Zoltan ;
Szabo, Laszlo ;
Mueller, Geza ;
Csernoch, Laszlo ;
Szentesi, Peter .
JOURNAL OF PHYSIOLOGY-LONDON, 2014, 592 (06) :1353-1365
[6]   Over-expression of Follistatin-like 3 attenuates fat accumulation and improves insulin sensitivity in mice [J].
Brandt, Claus ;
Hansen, Rasmus Huass ;
Hansen, Jakob Bondo ;
Olsen, Caroline Holkmann ;
Galle, Pia ;
Mandrup-Poulsen, Thomas ;
Gehl, Julie ;
Pedersen, Bente Klarlund ;
Hojman, Pernille .
METABOLISM-CLINICAL AND EXPERIMENTAL, 2015, 64 (02) :283-295
[7]   Marker-assisted introgression of the Compact mutant myostatin allele Mstn Cmpt-dl1Abc into a mouse line with extreme growth effects on body composition and muscularity [J].
Bünger, L ;
Ott, G ;
Varga, L ;
Schlote, W ;
Rehfeldt, C ;
Renne, U ;
Williams, JL ;
Hill, WG .
GENETICAL RESEARCH, 2004, 84 (03) :161-173
[8]  
Bünger L, 2001, MAMM GENOME, V12, P678, DOI 10.1007/s00335-001-3018-6
[9]   Myostatin regulates glucose metabolism via the AMP-activated protein kinase pathway in skeletal muscle cells [J].
Chen, Yuewen ;
Ye, Jianwei ;
Cao, Lingzhi ;
Zhang, Yong ;
Xia, Weibo ;
Zhu, Dahai .
INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY, 2010, 42 (12) :2072-2081
[10]   A mutation creating a potential illegitimate microRNA target site in the myostatin gene affects muscularity in sheep [J].
Clop, Alex ;
Marcq, Fabienne ;
Takeda, Haruko ;
Pirottin, Dimitri ;
Tordoir, Xavier ;
Bibe, Bernard ;
Bouix, Jacques ;
Caiment, Florian ;
Elsen, Jean-Michel ;
Eychenne, Francis ;
Larzul, Catherine ;
Laville, Elisabeth ;
Meish, Francoise ;
Milenkovic, Dragan ;
Tobin, James ;
Charlier, Carole ;
Georges, Michel .
NATURE GENETICS, 2006, 38 (07) :813-818