The inability to swallow, or dysphagia, is a debilitating and life-threatening disease that affects over 15 million Americans. Dysphagia results from dysfunction in the pharyngeal muscles, which are essential for proper swallowing and prevention of food/liquid aspiration into the lungs. Many studies have addressed the associated neuronal and neuromuscular component of pharyngeal dysfunction, yet the primary role of the affected pharyngeal muscles and their associated myogenic stem cells in dysphagia remains unknown. Adult muscle stem cells, called satellite cells, proliferate, differentiate and fuse with each other and existing myofibers during myogenesis. Myogenesis is critical for repair, growth, and maintenance of muscle tissue. Our preliminary data, assessing pharyngeal satellite cell number, proliferation and fusion, demonstrate an enhanced myogenic phenotype relative to the commonly studied satellite cells of the limb. These unusual myogenic properties suggest both pharyngeal muscles and their stem cell population are unique. We hypothesize that the enhanced myogenic phenotype of pharyngeal satellite cells is required to maintain proper pharyngeal structure and function throughout life, and that alteration of satellite cell function contributes to dysphagia. However, no studies examining pharyngeal satellite cell physiology exist. Therefore, in our first aim we will use an integrated in vivo/in vitro approach in mice to elucidate the critical physiological parameters of satellite cell number, proliferation, heterogeneity, and fusion.
Our second aim will address whether impairment of satellite cell function, via in vivo satellite cell ablation in mice, results in pharyngeal muscle pathology and a dysphagic phenotype. The long-term goal of these studies is two-fold: 1) to establish a fundamental, physiological understanding of an understudied stem cell population, pharyngeal satellite cells, and their contribution to pharyngeal muscle function;2) to determine if muscle stem cells could be a novel therapeutic target for patients suffering from life-threatening dysphagia. By understanding novel pathological mechanisms underlying dysphagia, potential life-enhancing therapies for dysphagic patients can be developed.
The inability to swallow is a debilitating and life-threatening condition that afflicts 15 million Americans. We seek to understand the normal properties of muscle stem cells that are associated with the muscles of the throat and to determine if muscle stem cells contribute to the ability to swallow. These studies will enhance the development of new life-enhancing therapies for people who cannot swallow.
|Randolph, Matthew E; Pavlath, Grace K (2015) A muscle stem cell for every muscle: variability of satellite cell biology among different muscle groups. Front Aging Neurosci 7:190|
|Randolph, Matthew E; Phillips, Brittany L; Choo, Hyo-Jung et al. (2015) Pharyngeal Satellite Cells Undergo Myogenesis Under Basal Conditions and Are Required for Pharyngeal Muscle Maintenance. Stem Cells 33:3581-95|
|Randolph, Matthew E; Luo, Qingwei; Ho, Justin et al. (2014) Ageing and muscular dystrophy differentially affect murine pharyngeal muscles in a region-dependent manner. J Physiol 592:5301-15|