Genetic regulation of muscle fiber diversity. The long-term goal of this project is to create a developmental regulatory framework to describe how diverse skeletal muscle fiber types are specified. Mammalian muscles contain distinct fiber types with unique physiologies; however the manner in which fiber-type development occurs has yet to be fully elucidated. We use the Drosophila system to understand mechanisms of muscle fiber differentiation, by analyzing the development of two distinct muscles in the adult thorax: the flight muscles and jump muscles, which are members of two distinct fiber types. In the current period of support, we discovered that the transcription factors Extradenticle (Exd) and Homothorax (Hth) activate a regulatory cascade involving another transcription factor, Spalt-major (Salm), and the CELF-related splicing factor Arrest (Aret). This network promotes specification of the flight muscles through direct activation of at least one flight muscle structual gene, and through direct regulation of flight muscle- specific alternative splicing events. Each factor can also promote flight muscle fate in the jump muscle, indicating that they are critical to fiber-specific gene regulation. Importantly, Exd, Hth and Aret have vertebrate homologs known to function in promoting fast fiber fate. In the next period of support, we will build upon this framework to generate a complete view of how fiber-specific identity is controlled, and expand our analysis to define how jump muscle differentiation is controlled. We will also investigate how the transcriptional pathways for formation of individual fiber types interact with one another to maintain their own identity, and to suppress formation of the other fiber type. Given that Exd, Hth and Aret each have vertebrate orthologs that contribute to fiber-specific gene regulation, our studies stand to provide critical new insight into mechanisms of muscle formation in vertebrates, and will generate a framework for understanding the basis of fiber-specific gene regulation in mammalian development and disease.

Public Health Relevance

Understanding the transcriptional programs that control muscle fiber specification is a major area of investigation in muscle biology. Moreover, a number of human muscle diseases preferentially affect one class of muscles over another. By defining mechanisms for how individual muscle arises in the body, our studies will provide a deeper understanding of how some muscles might be more sensitive to the development of pathologies, and how the symptoms of such diseases might be ameliorated. The Drosophila system has a noted history of being used to define basic cellular and molecular processes that function in development and disease in higher animals.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM061738-17
Application #
9394025
Study Section
Skeletal Muscle Biology and Exercise Physiology Study Section (SMEP)
Program Officer
Hoodbhoy, Tanya
Project Start
2001-05-01
Project End
2018-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
17
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of New Mexico
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
868853094
City
Albuquerque
State
NM
Country
United States
Zip Code
87106
Chechenova, Maria B; Maes, Sara; Oas, Sandy T et al. (2017) Functional redundancy and nonredundancy between two Troponin C isoforms in Drosophila adult muscles. Mol Biol Cell 28:760-770
Adema, Coen M; Hillier, LaDeana W; Jones, Catherine S et al. (2017) Whole genome analysis of a schistosomiasis-transmitting freshwater snail. Nat Commun 8:15451
Lovato, TyAnna L; Cripps, Richard M (2017) High Heart: A Role for Calcineurin Signaling in Hypoxia-Influenced Cardiac Growth. Circ Cardiovasc Genet 10:
Lovato, TyAnna L; Cripps, Richard M (2016) Regulatory Networks that Direct the Development of Specialized Cell Types in the Drosophila Heart. J Cardiovasc Dev Dis 3:
Chechenova, Maria B; Maes, Sara; Cripps, Richard M (2015) Expression of the Troponin C at 41C Gene in Adult Drosophila Tubular Muscles Depends upon Both Positive and Negative Regulatory Inputs. PLoS One 10:e0144615
Elwell, Jennifer A; Lovato, TyAnna L; Adams, Melanie M et al. (2015) The myogenic repressor gene Holes in muscles is a direct transcriptional target of Twist and Tinman in the Drosophila embryonic mesoderm. Dev Biol 400:266-76
Lovato, TyAnna L; Sensibaugh, Cheryl A; Swingle, Kirstie L et al. (2015) The Drosophila Transcription Factors Tinman and Pannier Activate and Collaborate with Myocyte Enhancer Factor-2 to Promote Heart Cell Fate. PLoS One 10:e0132965
Brunetti, Tonya M; Fremin, Brayon J; Cripps, Richard M (2015) Identification of singles bar as a direct transcriptional target of Drosophila Myocyte enhancer factor-2 and a regulator of adult myoblast fusion. Dev Biol 401:299-309
Oas, Sandy T; Bryantsev, Anton L; Cripps, Richard M (2014) Arrest is a regulator of fiber-specific alternative splicing in the indirect flight muscles of Drosophila. J Cell Biol 206:895-908
Chechenova, Maria B; Bryantsev, Anton L; Cripps, Richard M (2013) The Drosophila Z-disc protein Z(210) is an adult muscle isoform of Zasp52, which is required for normal myofibril organization in indirect flight muscles. J Biol Chem 288:3718-26

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