Muscle development in childhood and muscle regeneration in adults are dynamic processes that are necessary for reaching and maintaining optimal muscle mass and strength throughout life. Muscle repair after injury relies on stem cells (termed satellite cells), which when activated undergo sequential proliferation, differentiation, and fusion with existing myofibers. Satellite cell activity is controlled by complex signals mediated by cell-cell contact, by growth factors, and by hormones, which interact with genetic programs regulated by myogenic transcription factors. The physiologically critical loss of muscle mass and strength that occurs in aging and with chronic disease, termed sarcopenia, affects over 25% of elderly individuals, and accounts for medical costs in the billions. Therapy for sarcopenia is inadequate, primarily because mechanisms responsible for limiting muscle loss have not been elucidated. Insulin-like growth factors (IGFs) play key roles in muscle development and help coordinate muscle repair after injury. IGF actions can counteract inhibitory effects of other signaling molecules on muscle differentiation, and thus represent potentially powerful anabolic agents to reduce or reverse sarcopenia. This project will focus on mechanisms that stimulate muscle differentiation and repair through interactions with pathways regulated by the IGFs, with the goal of using this knowledge to promote long-term enhancement of muscle for therapeutic benefit. The following Specific Aims are proposed to develop these ideas: 1. To define interactions between the IGF-activated PI3-kinase - Akt signaling pathway and p38- regulated pathways. Goals are to delineate biochemical mechanisms that mediate potential cross talk and also define unique functions of each of these networks to promote muscle differentiation. 2. To elucidate mechanisms controlling Igf2 gene transcription during muscle differentiation. Goals are to determine if a putative muscle enhancer mapping >100 kb 3'to the Igf2 gene mediates Igf2 transcriptional activity during muscle differentiation in vitro, and during muscle growth and repair in vivo, and integrates signals from different environmental and genetic programs to regulate the first step in an IGF2-driven autocrine - paracrine muscle differentiation and growth pathway. Proposed studies have the potential to identify new treatment strategies for sarcopenia by establishing mechanisms to facilitate and coordinate activities of critical signal transduction networks that enhance muscle differentiation and stimulate myofiber formation.

Public Health Relevance

A major impediment in developing effective treatments for sarcopenia is lack of knowledge about fundamental relationships between critical signal transduction networks activated by hormones and growth factors, and intrinsic muscle regulatory programs controlled by myogenic transcription factors. As IGF actions play key roles in muscle regeneration following injury, and in sustaining muscle mass during aging and in disease, dissecting the biochemical mechanisms by which IGF-activated signaling pathways interact with myogenic regulatory proteins has potential therapeutic implications. Thus, understanding IGF actions in muscle should yield new insights that will define ways to facilitate muscle regeneration and reverse sarcopenia through selective manipulation of distinct signaling cascades.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Molecular and Cellular Endocrinology Study Section (MCE)
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Sato, Sheryl M
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Oregon Health and Science University
Schools of Medicine
United States
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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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