Skeletal muscle differentiation is a well-orchestrated process regulated by autocrine, paracrine, and endocrine factors via a regulatory network of signal transduction pathways. In recent years the mammalian target of rapamycin (mTOR) has begun to be recognized as a critical regulator of skeletal muscle differentiation, growth and hypertrophy. Work from our laboratory has contributed to the current understanding of mTOR regulation of myoblast differentiation, and has led to the revelation that mTOR regulates multiple stages of myogenesis by assembling distinct pathways, some of which unexpected and yet to be fully delineated. With a combination of biochemical, molecular, cellular and genetic approaches, and utilizing both in vitro and in vivo systems, we aim to fill a sizable gap in the current knowledge of molecular pathways underlying the regulation of skeletal myogenesis by addressing these three major questions: (1) How are the known components of growth-regulating mTOR pathway involved in myogenesis, and what is the mTOR pathway(s) that regulates the initiation of myoblast differentiation in response to amino acids availability signals? (2) What is the mTOR pathway that specifically regulates the second-stage myocyte fusion critical for myotube/myofiber growth and maturation, and which secreted factors regulate this process? (3) What is mTOR's role in muscle regeneration and what are the mechanisms? Our expertise in biochemical characterization of signal transduction mechanisms, our strong preliminary data, and the unique animal models we have created, put us in an ideal position to tackle those questions. Knowledge gained in these studies will contribute to the molecular understanding of skeletal muscle development, repair, regeneration and hypertrophy.

Public Health Relevance

Skeletal muscle differentiation is a well-orchestrated process regulated by autocrine, paracrine, and endocrine factors via multiple signal transduction pathways. Our proposed studies aim to dissect the molecular mechanisms underlying the regulation of skeletal muscle differentiation and regeneration, with a focus on the mammalian target of rapamycin signaling network. Knowledge gained in these studies will contribute to the molecular understanding of skeletal muscle biology, which may have significant impact on health-related issues such as muscular dystrophy, aging or disease-induced muscle atrophy, muscle regeneration, and exercise- induced muscle hypertrophy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR048914-10
Application #
8447110
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Boyce, Amanda T
Project Start
2002-07-01
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2015-02-28
Support Year
10
Fiscal Year
2013
Total Cost
$303,038
Indirect Cost
$104,404
Name
University of Illinois Urbana-Champaign
Department
Anatomy/Cell Biology
Type
Schools of Arts and Sciences
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
Khanna, Nidhi; Ge, Yejing; Chen, Jie (2014) MicroRNA-146b promotes myogenic differentiation and modulates multiple gene targets in muscle cells. PLoS One 9:e100657
Ge, Yejing; Waldemer, Rachel J; Nalluri, Ramakrishna et al. (2013) Flt3L is a novel regulator of skeletal myogenesis. J Cell Sci 126:3370-9
Ge, Yejing; Waldemer, Rachel J; Nalluri, Ramakrishna et al. (2013) RNAi screen reveals potentially novel roles of cytokines in myoblast differentiation. PLoS One 8:e68068
He, Yuan; Li, Dong; Cook, Sara L et al. (2013) Mammalian target of rapamycin and Rictor control neutrophil chemotaxis by regulating Rac/Cdc42 activity and the actin cytoskeleton. Mol Biol Cell 24:3369-80
Khanna, Nidhi; Fang, Yimin; Yoon, Mee-Sup et al. (2013) XPLN is an endogenous inhibitor of mTORC2. Proc Natl Acad Sci U S A 110:15979-84
Zhang, Chongben; Wendel, Angela A; Keogh, Matthew R et al. (2012) Glycerolipid signals alter mTOR complex 2 (mTORC2) to diminish insulin signaling. Proc Natl Acad Sci U S A 109:1667-72
Ge, Yejing; Yoon, Mee-Sup; Chen, Jie (2011) Raptor and Rheb negatively regulate skeletal myogenesis through suppression of insulin receptor substrate 1 (IRS1). J Biol Chem 286:35675-82
Jain, Ankur; Liu, Ruijie; Ramani, Biswarathan et al. (2011) Probing cellular protein complexes using single-molecule pull-down. Nature 473:484-8
Ge, Yejing; Sun, Yuting; Chen, Jie (2011) IGF-II is regulated by microRNA-125b in skeletal myogenesis. J Cell Biol 192:69-81
Yoon, Mee-Sup; Sun, Yuting; Arauz, Edwin et al. (2011) Phosphatidic acid activates mammalian target of rapamycin complex 1 (mTORC1) kinase by displacing FK506 binding protein 38 (FKBP38) and exerting an allosteric effect. J Biol Chem 286:29568-74

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