title: Extraocular muscle satellite cells are high performance myo-engines retaining efficient regenerative capacity in dystrophin deficiency.
abstract: Extraocular muscles (EOMs) are highly specialized skeletal muscles that originate from the head mesoderm and control eye movements. EOMs are uniquely spared in Duchenne muscular dystrophy and animal models of dystrophin deficiency. Specific traits of myogenic progenitors may be determinants of this preferential sparing, but very little is known about the myogenic cells in this muscle group. While satellite cells (SCs) have long been recognized as the main source of myogenic cells in adult muscle, most of the knowledge about these cells comes from the prototypic limb muscles. In this study, we show that EOMs, regardless of their distinctive Pax3-negative lineage origin, harbor SCs that share a common signature (Pax7(+), Ki67(-), Nestin-GFP(+), Myf5(nLacZ+), MyoD-positive lineage origin) with their limb and diaphragm somite-derived counterparts, but are remarkably endowed with a high proliferative potential as revealed in cell culture assays. Specifically, we demonstrate that in adult as well as in aging mice, EOM SCs possess a superior expansion capacity, contributing significantly more proliferating, differentiating and renewal progeny than their limb and diaphragm counterparts. These robust growth and renewal properties are maintained by EOM SCs isolated from dystrophin-null (mdx) mice, while SCs from muscles affected by dystrophin deficiency (i.e., limb and diaphragm) expand poorly in vitro. EOM SCs also retain higher performance in cell transplantation assays in which donor cells were engrafted into host mdx limb muscle. Collectively, our study provides a comprehensive picture of EOM myogenic progenitors, showing that while these cells share common hallmarks with the prototypic SCs in somite-derived muscles, they distinctively feature robust growth and renewal capacities that warrant the title of high performance myo-engines and promote consideration of their properties for developing new approaches in cell-based therapy to combat skeletal muscle wasting.
authors.affiliation: Department of Biological Structure, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: Pascal
authors.initials: P
authors.lastname: Stuelsatz
authors.affiliation: Department of Biological Structure, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Shearer
authors.affiliation: Department of Biological Structure, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: Yunfei
authors.initials: Y
authors.lastname: Li
authors.affiliation: Program in Molecular and Cellular Biology and Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: Lindsey A
authors.initials: LA
authors.lastname: Muir
authors.affiliation: Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Ieronimakis
authors.affiliation: Department of Biological Structure, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: Qingwu W
authors.initials: QW
authors.lastname: Shen
authors.affiliation: Department of Biological Structure, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Kirillova
authors.affiliation: Department of Biological Structure, University of Washington School of Medicine, Seattle, WA, USA. Electronic address: reuveni@uw.edu.
authors.forename: Zipora
authors.initials: Z
authors.lastname: Yablonka-Reuveni
mesh_terms: D000818:Animals; D019070:Cell Lineage; D049109:Cell Proliferation; D002469:Cell Separation; D017690:Cell Transplantation; D004195:Disease Models, Animal; D016189:Dystrophin / Q000172:deficiency / Q000502:physiology*; D005121:Extremities / Q000196:embryology; D005260:Female; D005434:Flow Cytometry; D018507:Gene Expression Regulation, Developmental; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000196:embryology*; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics; D012038:Regeneration / Q000502:physiology*; D032496:Satellite Cells, Skeletal Muscle / Q000166:cytology*; D013234:Stem Cells / Q000166:cytology*
chemical_list: D016189:Dystrophin
keywords: Clonal growth; Cre/loxP; Duchenne muscular dystrophy; Engraftment; Extraocular muscles; FACS; Mdx(4cv); Myf5; MyoD; Myosin light chain 3F-nLacZ; Nestin-GFP; Pax3; Pax7; Renewal; Retractor bulbi; Satellite cells