The Role of Pharyngeal Satellite Cells in Pharyngeal Muscle Biology Pubblico
Randolph, Matthew Emerson (2015)
Abstract
The inability to swallow, or dysphagia, is a debilitating and life-threatening condition that arises with aging or disease. The seven major pharyngeal muscles of the nasal, oral, and laryngeal pharynxes are required for swallowing. Interestingly, pharyngeal muscles are preferentially affected in some muscular dystrophies yet spared in others. Unique properties of pharyngeal muscles or their associated muscle stem cells, called satellite cells, may be critical factors in the development of pharyngeal muscle disorders; however, very little is known about the effects of disease and aging on pharyngeal muscles, nor the normal physiology of pharyngeal satellite cells (PSCs) and their role in pharyngeal muscles. We showed that aging affects pharyngeal muscle growth and atrophy in mice depending on the particular muscle analyzed. Wild-type mice also develop dysphagia with aging. Additionally, we studied pharyngeal muscles in a mouse model for oculopharyngeal muscular dystrophy, a dysphagic disease caused by a polyalanine expansion in the RNA binding protein, polyadenylate binding nuclear protein 1 (PABPN1). We examined pharyngeal muscles of mice overexpressing either wild-type or mutant PABPN1 and found overexpression of mutant PABPN1 differentially affected growth dependent on the anatomic location of muscles within the pharynx. Overexpression of wild-type PABPN1 was protective against age-related muscle atrophy in the laryngopharynx and prevented the development of age-related dysphagia. These results demonstrate that pharyngeal muscles are differentially affected by both aging and muscular dystrophy in a region-dependent manner. Our examination of PSCs revealed both transcriptional and biological differences from the commonly studied limb satellite cells. Under basal conditions PSCs proliferated, progressed through myogenesis, and fused with pharyngeal myofibers. Furthermore, PSCs also exhibited biologic differences dependent on anatomic location in the pharynx. Importantly, PSCs were required to maintain myofiber size and myonuclearnumber in pharyngeal myofibers. These results demonstrate that PSCs are critical for pharyngeal muscle maintenance and suggest that satellite cell impairment could contribute to pharyngeal muscle pathology associated with various muscular dystrophies and aging. These studies lay important groundwork for understanding the molecular and cellular mechanisms that regulate pharyngeal muscle maintenance, growth and atrophy, which could lead to novel therapies for individuals afflicted with dysphagia.
Table of Contents
Chapter 1: Introduction...1
Chapter 2: Background and Significance...5
2.1 Skeletal Muscle...6
2.1.1 Skeletal Muscle Structure and Function...6
2.1.2 Skeletal Muscle Regeneration...10
2.1.3 Skeletal Muscle Growth...12
2.2 Craniofacial Skeletal Muscle and Satellite Cell Biology...13
2.2.1 Embryologic Origins...13
2.2.2 Satellite Cells of Extraocular Muscles...14
2.2.3 Satellite Cells of Masseter Muscles...15
2.2.4 Satellite Cells of Tongue Muscles...15
2.3 Variable Susceptibility of Skeletal Muscles to Aging and Disease...16
2.3.1 Variable Effects of Aging on Skeletal Muscle...17
2.3.2 Variation in Myogenic Networks and Skeletal Muscle Disease...17
2.3.3 Variable Skeletal Muscle Susceptibility to Dystrophic Mutations...18
A. Duchenne Muscular Dystrophy...19
B. Limb-Girdle Muscular Dystrophy...20
C. Emery-Dreifuss Muscular Dystrophy...21
D. Facioscapulohumeral Muscular Dystrophy...21
E. Myotonic Dystrophy...22
F. Oculopharyngeal Muscular Dystrophy...23
2.4 Pharyngeal Skeletal Muscles and Satellite Cells: The Unknown...25
2.4.1 Pharyngeal Skeletal Muscles...26
2.4.2 Pharyngeal Satellite Cells...27
2.5 Summary...29
2.6 Figures...30
2.7 Table...36
Chapter 3: Materials and Methods...38
Chapter 4: Aging and muscular dystrophy differentially affect murine pharyngeal muscles in a region-dependent manner...53
4.1 Introduction...54
4.2 Results....57
4.3 Discussion...65
4.4 Figures...71
Chapter 5: Pharyngeal satellite cells undergo basal myogenesis and are required for pharyngeal muscle maintenance...83
5.1 Introduction...84
5.2 Results...87
5.3 Discussion...96
5.4 Figures...102
Chapter 6: Discussion...122
6.1 Introduction...123
6.2 Implications of Pharyngeal Myofiber Composition and Structure in Disease Predisposition...124
6.3 Implications of Pharyngeal Skeletal Muscle Growth and the Effects of Aging..126
6.4 Implications of Region-Dependent Effects of Muscular Dystrophy on Pharyngeal Muscle...127
6.5 Implications for PABPN1 Overexpression on Pharyngeal Muscle...129
6.6 Implications of Satellite Cells in Pharyngeal Muscle Maintenance...132
6.7 Functional Outcomes of Pharyngeal Satellite Cell Impairment...136
6.8 Implications of Regional Variation in Pharyngeal Muscle and Satellite Cell Biology...139
6.9 Current Difficulties With Pharyngeal Muscle Model Systems...139
6.10 Summary...141
6.11 Figures...144
6.12 Table...154
References...157
Appendix...194
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