Molecular Mechanisms of Aging in the Intrinsic Laryngeal Muscles

As individuals age, muscle weakness and neuromuscular disorders have the potential to diminish the quality of life, increase health care costs, and lead to institutionalization The larynx is part of a complex motor system that serves dually as the vibratory source of phonation and as a valve that separates and protects the airway from the digestive tract. In the elderly, age-related changes of intrinsic laryngeal muscles may compromise voice quality, thus, impair the ability to communicate and diminish the ability to remain socially engaged. Laryngeal dysfunction may also cause dysphagia and increase the risk of aspiration which may translate to higher mortality and morbidity. Our preliminary findings indicate that the intrinsic laryngeal muscles have a unique phenotype that is significantly altered by age. However, the biology of these small muscles remains largely unexplored. This project, in response to the NIDCD Small Grant (R03) Program, will achieve two objectives: (1) address a scientific issue; (2) provide a mechanism to further professional development of the PI, leading to independence. The studies will test the central hypothesis that aging disrupts the organization and stability of the neuromuscular junction in the intrinsic laryngeal muscles. Using the Fischer 344-Brown Norway F1 hybrid rat model of aging, the studies will examine to what extent aging alters NMJ organization in the posterior cricoarytenoid (PCA, vocal fold abductor) and thyroarytenoid (TA, vocal fold adductor) muscles. Three Specific Aims will be accomplished. Specific Aim 1 will test whether age changes NMJ ultrastructure and the expression of acetylcholine receptor subunits in the intrinsic laryngeal muscles. Specific Aim 2 will evaluate if aging represses cellular signaling pathways that initiate and sustain NMJ organization. Specific Aim 3 will assess to what extent age alters the acetylcholine vesicle release system in the presynaptic terminals of the laryngeal NMJs. This project will generate novel data on how age disrupts NMJ organization in the intrinsic laryngeal muscles, and will provide the bases for interventions aimed at preventing or reversing age-related neuromuscular dysfunction in these small muscles. In addition, the anticipated results will be of relevance to pathophysiological processes that affect NMJ structure and function such as myasthenia gravis and the Lambert-Eaton myasthenic syndrome.