Myostatin inhibits IGF-I-induced myotube hypertrophy through Akt

被引:163
作者
Morissette, Michael R. [2 ]
Cook, Stuart A. [3 ]
Buranasombati, Cattleya [2 ]
Rosenberg, Michael A. [2 ]
Rosenzweig, Anthony [1 ,2 ,4 ]
机构
[1] Beth Israel Deaconess Med Ctr, Ctr Life Sci, CardioVasc Inst, Boston, MA 02215 USA
[2] Harvard Univ, Sch Med, CardioVasc Inst, Boston, MA USA
[3] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Fac Med, London, England
[4] Harvard Stem Cell Inst, Cambridge, MA USA
来源
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY | 2009年 / 297卷 / 05期
基金
美国国家卫生研究院;
关键词
growth differentiation factor-8; muscle growth; C2C12; MYOFIBRILLAR PROTEIN-SYNTHESIS; SKELETAL-MUSCLE MASS; MYOBLAST DIFFERENTIATION; GENE CAUSES; GROWTH; PATHWAY; ACTIVATION; MUTATION; PROLIFERATION; REGULATOR;
D O I
10.1152/ajpcell.00043.2009
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Morissette MR, Cook SA, Buranasombati C, Rosenberg MA, Rosenzweig A. Myostatin inhibits IGF-I induced myotube hypertrophy through Akt. Am J Physiol Cell Physiol 297: C1124-C1132, 2009. First published September 16, 2009; doi:10.1152/ajpcell.00043.2009.-Myostatin is a highly conserved negative regulator of skeletal muscle growth. Loss of functional myostatin in cattle, mice, sheep, dogs, and humans results in increased muscle mass. The molecular mechanisms responsible for this increase in muscle growth are not fully understood. Previously, we have reported that phenylephrine-induced cardiac muscle growth and Akt activation are enhanced in myostatin knockout mice compared with controls. Here we report that skeletal muscle from myostatin knockout mice show increased Akt protein expression and overall activity at baseline secondary to an increase in Akt mRNA. We examined the functional role of myostatin modulation of Akt in C2C12 myotubes, a well-established in vitro model of skeletal muscle hypertrophy. Adenoviral overexpression of myostatin attenuated the insulin-like growth factor-I (IGF-I)-mediated increase in myotube diameter, as well as IGF-I-stimulated Akt phosphorylation. Inhibition of myostatin by overexpression of the NH2-terminal portion of myostatin was sufficient to increase myotube diameter and Akt phosphorylation. Coexpression of myostatin and constitutively active Akt (myr-Akt) restored the increase in myotube diameter. Conversely, expression of dominant negative Akt (dn-Akt) with the inhibitory myostatin propeptide blocked the increase in myotube diameter. Of note, ribosomal protein S6 phosphorylation and atrogin-1/muscle atrophy F box mRNA were increased in skeletal muscle from myostain knockout mice. Together, these data suggest myostatin regulates muscle growth at least in part through regulation of Akt.
引用
收藏
页码:C1124 / C1132
页数:9
相关论文
共 41 条
[1]   Down-Regulation of Akt/Mammalian Target of Rapamycin Signaling Pathway in Response to Myostatin Overexpression in Skeletal Muscle [J].
Amirouche, Adel ;
Durieux, Anne-Cecile ;
Banzet, Sebastien ;
Koulmann, Nathalie ;
Bonnefoy, Regis ;
Mouret, Catherine ;
Bigard, Xavier ;
Peinnequin, Andre ;
Freyssenet, Damien .
ENDOCRINOLOGY, 2009, 150 (01) :286-294
[2]   Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo [J].
Bodine, SC ;
Stitt, TN ;
Gonzalez, M ;
Kline, WO ;
Stover, GL ;
Bauerlein, R ;
Zlotchenko, E ;
Scrimgeour, A ;
Lawrence, JC ;
Glass, DJ ;
Yancopoulos, GD .
NATURE CELL BIOLOGY, 2001, 3 (11) :1014-1019
[3]   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
[4]   Transcriptional effects of chronic Akt activation in the heart [J].
Cook, SA ;
Matsui, T ;
Li, L ;
Rosenzweig, A .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (25) :22528-22533
[5]   Modulating skeletal muscle mass by postnatal, muscle-specific inactivation of the myostatin gene [J].
Grobet, L ;
Pirottin, D ;
Farnir, F ;
Poncelet, D ;
Royo, LJ ;
Brouwers, B ;
Christians, E ;
Desmecht, D ;
Coignoul, F ;
Kahn, R ;
Georges, M .
GENESIS, 2003, 35 (04) :227-238
[6]   A deletion in the bovine myostatin gene causes the double-muscled phenotype in cattle [J].
Grobet, L ;
Martin, LJR ;
Poncelet, D ;
Pirottin, D ;
Brouwers, B ;
Riquet, J ;
Schoeberlein, A ;
Dunner, S ;
Menissier, F ;
Massabanda, J ;
Fries, R ;
Hanset, R ;
Georges, M .
NATURE GENETICS, 1997, 17 (01) :71-74
[7]   The myostatin propeptide and the follistatin-related gene are inhibitory binding proteins of myostatin in normal serum [J].
Hill, JJ ;
Davies, MV ;
Pearson, AA ;
Wang, JH ;
Hewick, RM ;
Wolfman, NM ;
Qiu, YC .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (43) :40735-40741
[8]   Fast/glycolytic muscle fiber growth reduces fat mass and improves metabolic parameters in obese mice [J].
Izumiya, Yasuhiro ;
Hopkins, Teresa ;
Morris, Carl ;
Sato, Kaori ;
Zeng, Ling ;
Viereck, Jason ;
Hamilton, James A. ;
Ouchi, Noriyuki ;
LeBrasseur, Nathan K. ;
Walsh, Kenneth .
CELL METABOLISM, 2008, 7 (02) :159-172
[9]   Mechanisms involved in the inhibition of myoblast proliferation and differentiation by myostatin [J].
Joulia, D ;
Bernardi, H ;
Garandel, W ;
Rabenoelina, F ;
Vernus, B ;
Cabello, G .
EXPERIMENTAL CELL RESEARCH, 2003, 286 (02) :263-275
[10]   Mutations in myostatin (GDF8) in double-muscled Belgian blue and Piedmontese cattle [J].
Kambadur, R ;
Sharma, M ;
Smith, TPL ;
Bass, JJ .
GENOME RESEARCH, 1997, 7 (09) :910-916