Dysphagia is a difficulty in swallowing which is observed in 20% of the elderly and several forms of muscular dystrophy patients and causes malnutrition and potential life threatening effects such as choking or pneumonia by aspiration of food; however, no cure or therapeutic treatment exists. Tongue and pharyngeal muscles are essential for proper swallowing and prevention of food/water aspiration into the lungs yet the cellular mechanisms that underlie changes in tongue and pharyngeal muscle function with age and with diseases, such as oculopharyngeal muscular dystrophy (OPMD), are unknown. OPMD is a late-onset, autosomal dominant muscle disease with prominent dysfunction of the eyelid, tongue and pharyngeal muscles; however, little is known about the mechanisms underlying the muscle-specificity of this disease. Muscle stem cells (satellite cells, SC) of craniofacial muscles have unique myogenic properties such as chronic high levels of proliferation and fusion with the myofiber in the absence of injury. Despite high and constant levels of myonuclear addition into myofibers by chronic satellite cell fusion, a constant number of myonuclei per myofiber is maintained, implying a high level of myonuclei turnover is occurring. This unusual myonuclear homeostasis may make craniofacial muscles more vulnerable to specific diseases and age. We propose 3 lines of experimentation addressing the cellular mechanisms underlying myonuclear homeostasis of craniofacial muscles. These studies will help identify mechanisms involved in the specificity of affected muscles in OPMD and provide potential targeted therapeutic strategies for dysphagia.
Aim 1 : To compare the effect of fibroadipogenic progenitor cells (FAPs) on satellite cell fusion with myofibers between craniofacial and limb muscles. We will determine whether muscle-specific FAP differences influence satellite cell (SC) proliferation or differentiation at different ages in mice using assays in vitro and in vivo.
Aim 2 : To quantify myonuclear turnover in craniofacial muscles and examine autophagy as a mechanism for myonuclear turnover. We will apply BrdU labeling methods to measure myonuclear turnover of craniofacial muscles and compare to the level of myonuclear addition with aging. Autophagy, which has a role in cellular homeostasis, will be examined as a potential mechanism for myonuclear turnover in craniofacial muscles.
Aim 3 : To determine the mechanism of impaired myonuclear addition in oculopharyngeal muscular dystrophy (OPMD) and whether myonuclear turnover is also altered. We will test whether the intrinsic myogenic potential of SC or the extrinsic effect of FAPs on the SCs influences impaired nuclear addition in craniofacial muscles in OPMD. In addition, we will measure the myonuclear turnover of craniofacial muscles in OPMD mice and determine whether augmentation of autophagy signaling affects myonuclear turnover and pathology in OPMD.
Oculopharyngeal muscular dystrophy (OPMD) is a late-onset disease characterized by difficulties in swallowing, which impairs the quality of life in patients due to frequent aspiration pneumonia together with malnutrition. The craniofacial muscles are the main affected muscles in specific myopathies, including OPMD; however, the mechanism of this muscle specificity is not understood. We will study the distinct myonuclear homeostasis of craniofacial muscles and their role in OPMD pathology, which provide the opportunity to understand the mechanisms of muscle-specificity in OPMD and develop targeted therapeutic strategies for these craniofacial- specific muscular disorders.