Muscle Structure Influences Utrophin Expression in mdx Mice

Banks, Glen B.; Combs, Ariana C.; Odom, Guy L.; Bloch, Robert J.; Chamberlain, Jeffrey S.

doi:10.1371/journal.pgen.1004431

Cited by 30 publications

(44 citation statements)

References 120 publications

(136 reference statements)

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“…Indeed, while we observed extensive abnormal morphologies (branching, internal splitting, bifurcation) in most EDL myofibers by 12–16 weeks of age in mdx 4cv mice (Fig. S5E–H; see also Banks et al, 2014 for similar conclusions), such level of malformations was observed in “standard” mdx mice only when reaching 26 weeks of age, while less than 5% of the myofibers displayed abnormalities by 15 weeks of age (Head et al, 1992; Williams, 1993). However, a side by side comparison between mdx 4cv , mdx and wildtype mice, looking at SC clonal growth, myofiber abnormalities and whole muscle regenerative capacity is yet to be performed.…”

Section: Resultssupporting

confidence: 67%

Extraocular muscle satellite cells are high performance myo-engines retaining efficient regenerative capacity in dystrophin deficiency

Stuelsatz

Shearer

et al. 2015

Developmental Biology

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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+, Myf5nLacZ+, 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.

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Section: Resultssupporting

confidence: 67%

Extraocular muscle satellite cells are high performance myo-engines retaining efficient regenerative capacity in dystrophin deficiency

Stuelsatz

Shearer

et al. 2015

Developmental Biology

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“…; Banks et al. ). This scenario is highly unlikely for the DysC‐Neg fibers in normal human palate muscles.…”

Section: Discussionmentioning

confidence: 97%

Unique expression of cytoskeletal proteins in human soft palate muscles

et al. 2015

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The human oropharyngeal muscles have a unique anatomy with diverse and intricate functions. To investigate if this specialization is also reflected in the cytoarchitecture of muscle fibers, intermediate filament proteins and the dystrophin-associated protein complex have been analyzed in two human palate muscles, musculus uvula (UV) and musculus palatopharyngeus (PP), with immunohistochenmical and morphological techniques. Human limb muscles were used as reference. The findings show that the soft palate muscle fibers have a cytoskeletal architecture that differs from the limb muscles. While all limb muscles showed immunoreaction for a panel of antibodies directed against different domains of cytoskeletal proteins desmin and dystrophin, a subpopulation of palate muscle fibers lacked or had a faint immunoreaction for desmin (UV 11.7% and PP 9.8%) and the C-terminal of the dystrophin molecule (UV 4.2% and PP 6.4%). The vast majority of these fibers expressed slow contractile protein myosin heavy chain I. Furthermore, an unusual staining pattern was also observed in these fibers for β-dystroglycan, caveolin-3 and neuronal nitric oxide synthase nNOS, which are all membrane-linking proteins associated with the dystrophin C-terminus. While the immunoreaction for nNOS was generally weak or absent, β-dystroglycan and caveolin-3 showed a stronger immunostaining. The absence or a low expression of cytoskeletal proteins otherwise considered ubiquitous and important for integration and contraction of muscle cells indicate a unique cytoarchitecture designed to meet the intricate demands of the upper airway muscles. It can be concluded that a subgroup of muscle fibers in the human soft palate appears to have special biomechanical properties, and their unique cytoarchitecture must be taken into account while assessing function and pathology in oropharyngeal muscles.

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“…Muscle structure influences utrophin expression in the mdx mouse (17,144). In slow/oxidative muscle, utrophin levels are elevated (50) and may contribute to enhancing the resistance of slow muscle fibers to contraction-induced damage in DMD (59,169,232).…”

Section: Utrophin Modulationmentioning

confidence: 99%

The Pathogenesis and Therapy of Muscular Dystrophies

Guiraud

Aartsma‐Rus

Vieira

et al. 2015

Annu. Rev. Genom. Hum. Genet.

257

286

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Current molecular genomic approaches to human genetic disorders have led to an explosion in the identification of the genes and their encoded proteins responsible for these disorders. The identification of the gene altered by mutations in Duchenne and Becker muscular dystrophy was one of the earliest examples of this paradigm. The nearly 30 years of research partly outlined here exemplifies the road that similar current gene discovery protocols will be expected to travel, albeit much more rapidly owing to improved diagnosis of genetic disorders and an understanding of the spectrum of mutations thought to cause them. The identification of the protein dystrophin has led to a new understanding of the muscle cell membrane and the proteins involved in membrane stability, as well as new candidate genes for additional forms of muscular dystrophy. Animal models identified with naturally occurring mutations and developed by genetic manipulation have furthered the understanding of disease progression and underlying pathology. The biochemistry and molecular analysis of patient samples have led to the different dystrophin-dependent and -independent therapies that are currently close to or in human clinical trials. The lessons learned from decades of research on dystrophin have benefited the field of human genetics.

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Muscle Structure Influences Utrophin Expression in mdx Mice

Cited by 30 publications

References 120 publications

Extraocular muscle satellite cells are high performance myo-engines retaining efficient regenerative capacity in dystrophin deficiency

Extraocular muscle satellite cells are high performance myo-engines retaining efficient regenerative capacity in dystrophin deficiency

Unique expression of cytoskeletal proteins in human soft palate muscles

The Pathogenesis and Therapy of Muscular Dystrophies

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