Histopathological marks of tongue in a mouse model for oculopharyngeal muscular dystrophy suggest biomechanical defects.

Abstract

The tongue facilitates vital activities such as swallowing. Swallowing difficulties (dysphagia) are common in the elderly and in many adult-onset neuromuscular diseases. In oculopharyngeal muscular dystrophy (OPMD), dysphagia is often the first symptom. OPMD is an autosomal dominant myopathy caused by a trinucleotide expansion mutation in the gene encoding PABPN1. The expanded PABPN1 forms insoluble nuclear aggregates that reduce the levels of the soluble form. Clinical tongue involvement in OPMD has been documented but is poorly understood. Histopathology of the tongue in OPMD mouse models was investigated by light and electron microscopy combined with RNA sequencing. PABPN1 nuclear aggregates were found at moderate levels, whereas deposition of insoluble PABPN1 in blood vessels was prominent already in 4-month-old mice. Muscle wasting in the tongue was age-associated. RNA signatures of the OPMD tongue were enriched for mitochondrial and cytoskeletal genes. Electron microscopy revealed abnormalities in sarcomere and mitochondria organization in A17/+, suggesting an energy and contractile deficit in OPMD tongue. This detailed analysis of the histopathology of the tongue in the A17/+ mouse model opens new avenues for understanding the mechanisms of dysphagia.