This renewal represents an expansion of the previous application with a new focus on exploring the anatomical and biochemical specializations of the pharyngeal dilator (genioglossus, GG), pharyngeal constrictors (PCs), upper esophageal sphincter (UES) and palatal muscles in: 1) 0-3 years old and 70-85 years old humans; 2) pathological human specimens with idiopathic Parkinson's disease (IPD); and 3) adult macaque monkey. The long-term goal of this application is to improve our understanding of the neuromuscular control of the upper airway functions and of the mechanisms causing dysphagia and obstructive sleep apnea in an effort to develop novel therapies for treating both life-threatening disorders. The pharyngeal muscles play vital roles in maintenance of upper airway patency and pharyngeal swallowing. Dysfunction of these muscles is related to the occurrence of upper airway disorders. However, the pathogenesis of these disorders remains poorly understood. Our preliminary studies showed that the adult human GG was divided into slow horizontal and fast oblique compartments. The PCs and UES were composed of a slow inner layer and a fast outer layer which were innervated by the IX and X nerves, respectively. It is interesting to note that the histochemically defined fiber layers in the PCs were obscured with aging. Another important finding was that the adult pharyngeal muscles contained muscle fibers expressing unusual myosin heavy chain (MHC) isoforms (slow-tonic and alpha-cardiac) which were concentrated predominantly in the slow horizontal GG and slow inner layer of the PCs. Based on these novel observations, we hypothesize that the adult human pharyngeal muscles have been specialized as a result of functional demands and that differences in the fiber type and MHC composition in the pharyngeal muscles exist between different age groups of normal humans, between normal adult human and IPD, and between human and non-human primates. The hypotheses will be tested with the following 2 specific aims. Specific Aim 1 is to determine the neuromuscular compartments within the GG, PCs, UES, and palatal muscles using current anatomical and histochemical criteria. The muscular organization, nerve supply patterns, banding patterns and types of the motor endplates, and fibertype distribution will be determined using whole-mount nerve staining (i.e., Sihler's stain), acetylcholinesterase and silver stain, and myofibrillar ATPase staining. Specific Aim 2 is to study the intrinsic properties of the muscle fibers in each of the muscles and/or compartments. The major and unusual MHC isoforms in muscle fibers in a given muscle and/or compartment will be detected using immunocytochemistry, whole muscle and/or single fiber electrophoresis, and immunoblotting techniques. The metabolic capacity of the MHC-based various fiber types in each muscle and/or compartment will be studied using enzyme-histochemical methods. Overall, the proposed studies will provide important data about the age-related, species-dependent and pathologically induced changes in the neuromuscular properties of the pharyngeal muscles. This knowledge will enhance our understanding of the anatomical and biochemical basis of the mechanisms involved in neuromuscular control of the pharyngeal swallowing, speech and respiration. The data may help to guide treatment strategies that are aimed at using implantable pharyngeal muscle nerve stimulators to alleviate dysphagia and airway obstruction during sleep.