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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK042748-24A1
Application #
8626996
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Sato, Sheryl M
Project Start
1991-01-01
Project End
2018-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
24
Fiscal Year
2014
Total Cost
$434,972
Indirect Cost
$135,222
Name
Oregon Health and Science University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Gross, Sean M; Rotwein, Peter (2016) Unraveling Growth Factor Signaling and Cell Cycle Progression in Individual Fibroblasts. J Biol Chem 291:14628-38
Alzhanov, Damir; Rotwein, Peter (2016) Characterizing a distal muscle enhancer in the mouse Igf2 locus. Physiol Genomics 48:167-72
Gross, Sean M; Rotwein, Peter (2015) Akt signaling dynamics in individual cells. J Cell Sci 128:2509-19
Rotwein, Peter S (2015) Editorial: is it time for an evolutionarily based human endocrinology? Mol Endocrinol 29:487-9
Gardner, Samantha; Gross, Sean M; David, Larry L et al. (2015) Separating myoblast differentiation from muscle cell fusion using IGF-I and the p38 MAP kinase inhibitor SB202190. Am J Physiol Cell Physiol 309:C491-500
Rotwein, Peter (2014) Editorial: the fall of mechanogrowth factor? Mol Endocrinol 28:155-6
Mukherjee, Aditi; Larson, Emily A; Klein, Robert F et al. (2014) Distinct actions of akt1 on skeletal architecture and function. PLoS One 9:e93040
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
Gross, Sean M; Rotwein, Peter (2013) Live cell imaging reveals marked variability in myoblast proliferation and fate. Skelet Muscle 3:10
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

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