The differentiation, maturation, and maintenance of a complex tissue such as skeletal muscle requires ongoing cooperation between signaling pathways activated by hormones and growth factors, and intrinsic regulatory programs controlled by myogenic transcription factors. Insulin-like growth factors (IGFs) play key roles in normal muscle development in the fetus, are important for coordinating muscle regeneration following injury in the adult, and are critical for maintaining muscle mass during aging and in disease. The focus of this application will be on the IGF system in muscle development and repair, and represents part of a long-term effort to understand the mechanisms by which actions of the IGFs, their receptors, and binding proteins are integrated within the cell and in the whole organism. Based on current observations, we have postulated the existence of a robust autocrine signaling network in muscle cells that is critical for differentiation. The first key step in activating this network is production and secretion of IGF-II by differentiating myoblasts, which is secondary to induction of IGF-II gene transcription. Secreted IGF-II binds to and activates the IGF-I receptor, which leads to sustained stimulation of the PI3-kinase - Akt signaling pathway. Akt activity, principally Akt1, then plays a central role in driving early differentiation, in part by enhancing muscle gene expression through stabilization of active transcriptional complexes on muscle promoters. As differentiation proceeds, signal amplification occurs as more Akt2 is produced, and both Akts then participate in muscle cell maturation and in myocyte fusion to form multinucleated myotubes. I propose the following three Specific Aims to test this IGF-mediated signaling network hypothesis: 1. To determine the mechanisms of action of Akt1 in muscle differentiation. Proposed studies will test the idea that Akt1 is an obligate mediator of myoblast differentiation, and that its major functions are to enhance the actions of myogenic transcription factors on muscle gene promoters by stimulating key co-activators and inhibiting critical co-repressors. 2. To define the actions of Akt2 in muscle differentiation. Proposed experiments will examine the hypothesis that Akt2 acts to control late events in myoblast maturation and myotube formation. 3. To elucidate mechanisms of regulation of IGF-II gene transcription during muscle differentiation. Proposed experiments will test the hypothesis that a critical control region for differentiation-dependent activation of IGF-II gene transcription resides downstream of the H19 gene. Major goals will be to define the mechanisms of action of this chromosomal response element.

Public Health Relevance

Insulin-like growth factors (IGFs) play key roles in normal muscle development in the fetus, are important for coordinating muscle regeneration following injury in the adult, and are critical for maintaining muscle mass during aging and in disease. The focus of this application will be on the IGF system in muscle development and repair, and represents part of a long-term effort to understand the mechanisms by which actions of the IGFs, their receptors, and binding proteins are integrated within the cell and in the whole organism.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK042748-23
Application #
8208159
Study Section
Special Emphasis Panel (ZRG1-EMNR-H (02))
Program Officer
Sato, Sheryl M
Project Start
1991-01-01
Project End
2012-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
23
Fiscal Year
2012
Total Cost
$461,493
Indirect Cost
$161,822
Name
Oregon Health and Science University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Mukherjee, Aditi; Larson, Emily A; Klein, Robert F et al. (2014) Distinct actions of akt1 on skeletal architecture and function. PLoS One 9:e93040
Rotwein, Peter (2014) Editorial: the fall of mechanogrowth factor? Mol Endocrinol 28:155-6
Nili, Mahta; David, Larry; Elferich, Johannes et al. (2013) Proteomic analysis and molecular modelling characterize the iron-regulatory protein haemojuvelin/repulsive guidance molecule c. Biochem J 452:87-95
Mukherjee, Aditi; Larson, Emily A; Carlos, Amy S et al. (2012) Congenic mice provide in vivo evidence for a genetic locus that modulates intrinsic transforming growth factor ?1-mediated signaling and bone acquisition. J Bone Miner Res 27:1345-56
Nili, Mahta; Mukherjee, Aditi; Shinde, Ujwal et al. (2012) Defining the disulfide bonds of insulin-like growth factor-binding protein-5 by tandem mass spectrometry with electron transfer dissociation and collision-induced dissociation. J Biol Chem 287:1510-9
Mukherjee, Aditi; Rotwein, Peter (2012) Selective signaling by Akt1 controls osteoblast differentiation and osteoblast-mediated osteoclast development. Mol Cell Biol 32:490-500
Gardner, Samantha; Alzhanov, Damir; Knollman, Paul et al. (2011) TGF-? inhibits muscle differentiation by blocking autocrine signaling pathways initiated by IGF-II. Mol Endocrinol 25:128-37
Mukherjee, Aditi; Wilson, Elizabeth M; Rotwein, Peter (2010) Selective signaling by Akt2 promotes bone morphogenetic protein 2-mediated osteoblast differentiation. Mol Cell Biol 30:1018-27
Nili, Mahta; Shinde, Ujwal; Rotwein, Peter (2010) Soluble repulsive guidance molecule c/hemojuvelin is a broad spectrum bone morphogenetic protein (BMP) antagonist and inhibits both BMP2- and BMP6-mediated signaling and gene expression. J Biol Chem 285:24783-92
Alzhanov, Damir T; McInerney, Stephanie F; Rotwein, Peter (2010) Long range interactions regulate Igf2 gene transcription during skeletal muscle differentiation. J Biol Chem 285:38969-77

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