Extraocular muscles (EOMs) are a group of highly specialized skeletal muscles that control eye movements. They develop from the head mesoderm and are molecularly, anatomically and physiologically distinct from other skeletal muscles. EOMs possess a unique quality of being spared in muscular dystrophies associated with impairments in the dystrophin-glycoprotein complex. In Duchenne muscular dystrophy and in animal models of this devastating dystrophin deficiency-associated disease, EOMs are spared, contrary to the severe early- or late-onset damage to other muscles. Specific traits of myogenic progenitors in EOMs may play a role in the preferential sparing of these muscles. Surprisingly, very little is known about the myogenic stem and progenitor cells in adult EOMs. The difficulty in isolating EOMs for harvesting primary cells has resulted in the lack of appropriate cell culture models aimed at identifying the properties of cells that support EOM myofiber maintenance through life. This application proposes to decipher cellular and molecular characteristics of three cell types that display robust growth and renewal properties in EOMs compared to limb and diaphragm muscles, a distinction that may contribute to the sparing of EOMs from dystrophinopathy and age-linked atrophy. These cell types are: a) satellite cells, which are classically recognized as the main source of myogenic progenitors in adult skeletal muscle;b) interstitial myogenic progenitors;c) microvascular-associated contractile cells (i.e., pericytes), which may fuse directly with myofibers. The proposed studies aim to: 1) characterize myogenic-specific marker expression by cells in the satellite cell and interstitium niches of EOMs versus limb and diaphragm muscles;2) compare growth and renewal potential of myogenic stem and progenitor cells in EOMs versus limb and diaphragm muscles;3) investigate the potential of donor satellite cells and pericytes from EOMs versus limb and diaphragm muscles to contribute to in vivo muscle repair. Cells from wildtype and dystrophin-null mice that carry various reporter genes (for tracing the different cell types and their progeny) will be investigated in vivo and in culture. The expected results of the proposed studies will contribute to a better understanding of the cellular milieu that supports EOM maintenance in adult life and will provide new insights regarding the role of microvasculature-associated cells in skeletal myogenesis. Further characterization of EOM myogenic progenitors is essential for developing repair strategies to treat extraocular muscle disorders. The proposed studies will also shed new light on the functional status of myogenic progenitors in aging and dystrophin-deficient muscles, providing important information for muscle rehabilitation strategies.

Public Health Relevance

Extraocular muscles (EOMs) are a group of highly specialized skeletal muscles that control eye movements. Specific traits of myogenic progenitors in EOMs may have significance as determinants of the preferential sparing of this muscle group in muscular dystrophy, but surprisingly, very little is known about the EOM myogenic cell pool. The results of the proposed studies will contribute to a better understanding of the myogenic stem and progenitor cells that support EOM repair in adult life and will provide important information for muscle rehabilitation strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG035377-05
Application #
8509560
Study Section
Special Emphasis Panel (ZRG1-MOSS-H (04))
Program Officer
Williams, John
Project Start
2009-08-01
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2013
Total Cost
$287,580
Indirect Cost
$103,234
Name
University of Washington
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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