Selective Control of Skeletal Muscle Differentiation by Akt1*

The phosphatidylinositol 3-kinase-Akt pathway plays a central role in growth, development, and metabolism in both normal and neoplastic cells. In skeletal muscle, Akt has been implicated in regulating regeneration and hypertrophy and in counteracting atrophy. Here we provide evidence that Akt1 and not Akt2 is essential for muscle differentiation. Using a robust model of MyoD-mediated muscle development, in which dominant-negative Akt blocked differentiation, we show that targeted loss of Akt1 was equally inhibitory. Selective elimination of Akt1 had no effect on myoblast viability or proliferation but prevented differentiation by impairing the transcriptional actions of MyoD. In contrast, knockdown of Akt2 had no effect on myoblast survival or differentiation and minimally inhibited MyoD-regulated transcription. Our results define isoform-specific Akt-regulated signaling pathways in muscle cells that act through Akt1 to sustain muscle gene activation and promote differentiation.

[1]  E. Wilson,et al.  Control of MyoD Function during Initiation of Muscle Differentiation by an Autocrine Signaling Pathway Activated by Insulin-like Growth Factor-II* , 2006, Journal of Biological Chemistry.

[2]  H. Koistinen,et al.  siRNA-based gene silencing reveals specialized roles of IRS-1/Akt2 and IRS-2/Akt1 in glucose and lipid metabolism in human skeletal muscle. , 2006, Cell metabolism.

[3]  R. Pierce,et al.  AKT1 Provides an Essential Survival Signal Required for Differentiation and Stratification of Primary Human Keratinocytes* , 2006, Journal of Biological Chemistry.

[4]  M. Hall,et al.  TOR Signaling in Growth and Metabolism , 2006, Cell.

[5]  J. Brugge,et al.  Distinct roles of Akt1 and Akt2 in regulating cell migration and epithelial–mesenchymal transition , 2005, The Journal of cell biology.

[6]  W. Wahli,et al.  Dosage-Dependent Effects of Akt1/Protein Kinase Bα (PKBα) and Akt3/PKBγ on Thymus, Skin, and Cardiovascular and Nervous System Development in Mice , 2005, Molecular and Cellular Biology.

[7]  A. Toker,et al.  Akt blocks breast cancer cell motility and invasion through the transcription factor NFAT. , 2005, Molecular cell.

[8]  D. Yee,et al.  Type I insulin-like growth factor receptor as a therapeutic target in cancer. , 2005, Cancer research.

[9]  In-Hyun Park,et al.  Mammalian Target of Rapamycin (mTOR) Signaling Is Required for a Late-stage Fusion Process during Skeletal Myotube Maturation*[boxs] , 2005, Journal of Biological Chemistry.

[10]  J. Woodgett.  Recent advances in the protein kinase B signaling pathway. , 2005, Current opinion in cell biology.

[11]  T. Ludwig,et al.  Role for Akt3/Protein Kinase Bγ in Attainment of Normal Brain Size , 2005, Molecular and Cellular Biology.

[12]  K. Hruska,et al.  Akt1/Akt2 and Mammalian Target of Rapamycin/Bim Play Critical Roles in Osteoclast Differentiation and Survival, Respectively, Whereas Akt Is Dispensable for Cell Survival in Isolated Osteoclast Precursors* , 2005, Journal of Biological Chemistry.

[13]  E. Wilson,et al.  Gene disruption by regulated short interfering RNA expression, using a two-adenovirus system. , 2004, Human gene therapy.

[14]  G. Yancopoulos,et al.  Conditional Activation of Akt in Adult Skeletal Muscle Induces Rapid Hypertrophy , 2004, Molecular and Cellular Biology.

[15]  Eric P Hoffman,et al.  Balancing muscle hypertrophy and atrophy , 2004, Nature Medicine.

[16]  D. Accili,et al.  FoxOs at the Crossroads of Cellular Metabolism, Differentiation, and Transformation , 2004, Cell.

[17]  G. Yancopoulos,et al.  The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors. , 2004, Molecular cell.

[18]  B. Hemmings,et al.  Advances in protein kinase B signalling: AKTion on multiple fronts. , 2004, Trends in biochemical sciences.

[19]  C. Holding,et al.  Akt2, a Novel Functional Link between p38 Mitogen-Activated Protein Kinase and Phosphatidylinositol 3-Kinase Pathways in Myogenesis , 2004, Molecular and Cellular Biology.

[20]  Marco Sandri,et al.  Foxo Transcription Factors Induce the Atrophy-Related Ubiquitin Ligase Atrogin-1 and Cause Skeletal Muscle Atrophy , 2004, Cell.

[21]  E. Wilson,et al.  Permissive roles of phosphatidyl inositol 3-kinase and Akt in skeletal myocyte maturation. , 2003, Molecular biology of the cell.

[22]  M. Birnbaum,et al.  Isoform-specific Regulation of Insulin-dependent Glucose Uptake by Akt/Protein Kinase B* , 2003, Journal of Biological Chemistry.

[23]  E. Wilson,et al.  Autocrine Growth Factor Signaling by Insulin-like Growth Factor-II Mediates MyoD-stimulated Myocyte Maturation* , 2003, Journal of Biological Chemistry.

[24]  D. Accili,et al.  Regulation of insulin-like growth factor–dependent myoblast differentiation by Foxo forkhead transcription factors , 2003, The Journal of cell biology.

[25]  Jennifer Skeen,et al.  Dwarfism, impaired skin development, skeletal muscle atrophy, delayed bone development, and impeded adipogenesis in mice lacking Akt1 and Akt2. , 2003, Genes & development.

[26]  G. Grosveld,et al.  FKHR (FOXO1a) is required for myotube fusion of primary mouse myoblasts , 2003, The EMBO journal.

[27]  M. Tatar,et al.  The Endocrine Regulation of Aging by Insulin-like Signals , 2003, Science.

[28]  D. Glass.  Signalling pathways that mediate skeletal muscle hypertrophy and atrophy , 2003, Nature Cell Biology.

[29]  S. Nicosia,et al.  Positive Feedback Regulation between Akt2 and MyoD during Muscle Differentiation , 2002, The Journal of Biological Chemistry.

[30]  E. Calabria,et al.  A protein kinase B-dependent and rapamycin-sensitive pathway controls skeletal muscle growth but not fiber type specification , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[31]  A. Musarò,et al.  Muscle-specific expression of insulin-like growth factor I counters muscle decline in mdx mice , 2002, The Journal of cell biology.

[32]  G. Yancopoulos,et al.  Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo , 2001, Nature Cell Biology.

[33]  M. Birnbaum,et al.  Akt1/PKBα Is Required for Normal Growth but Dispensable for Maintenance of Glucose Homeostasis in Mice* , 2001, The Journal of Biological Chemistry.

[34]  K. Kaestner,et al.  Insulin Resistance and a Diabetes Mellitus-Like Syndrome in Mice Lacking the Protein Kinase Akt2 (PKBβ) , 2001 .

[35]  B. Hemmings,et al.  Protein Kinase B β/Akt2 Plays a Specific Role in Muscle Differentiation* , 2001, The Journal of Biological Chemistry.

[36]  M. Lawlor,et al.  Coordinate Control of Muscle Cell Survival by Distinct Insulin-like Growth Factor Activated Signaling Pathways , 2000, The Journal of cell biology.

[37]  J. Testa,et al.  Cell Cycle Withdrawal Promotes Myogenic Induction of Akt, a Positive Modulator of Myocyte Survival , 1999, Molecular and Cellular Biology.