Activation of mTOR coincides with autophagy during ligation-induced atrophy in the rat submandibular gland

Abstract

Salivary gland atrophy is a common consequence of pathology, including Sjögren's syndrome, irradiation therapy and obstructive sialadenitis. During severe atrophy of the rat submandibular gland caused by excretory duct ligation, the majority of acinar cells disappear through apoptosis, whereas ductal cells proliferate and dedifferentiate; yet, the gland can survive in the atrophic state almost indefinitely, with an ability to fully recover if deligated. The control mechanisms governing these observations are not well understood. We report that ∼10% of acinar cells survive in ligation-induced atrophy. Microarray and quantitative real-time PCR analysis of ligated glands indicated sustained transcription of acinar cell-specific genes, whereas ductal-specific genes were reduced to background levels. After 3 days of ligation, activation of the mammalian target of rapamycin (mTOR) pathway and autophagy occurred as shown by phosphorylation of 4E-BP1 and expression of autophagy-related proteins. These results suggest that activation of mTOR and the autophagosomal pathway are important mechanisms that may help to preserve acinar cells during atrophy of salivary glands after injury.

Altered autophagy and sympathetic innervation in salivary glands from high-fat diet mice

“…However in submandibular gland increased autophagy is associated with ligationinduced atrophic degeneration. 21 However there were no obvious histological signs of atrophy and most likely the increased autophagy is due to increased processing of lipids.…”

“…18,19 In most normal healthy tissues such as liver and muscle, mTOR is active and drives protein synthesis. In salivary glands it is normally inactive but becomes activated with atrophy 20,21 However the effect of diet on salivary glands regarding mTOR pathway has not been elucidated.…”

Expression of a Neural Stem/Progenitor Cell Marker Nestin in Salivary Glands

“…12 Salivary gland atrophy is a common consequence of disease and injury, such as radiation treatment, Sjögren's syndrome, and sialadenitis, and a reduction in the number of normal acinar cells causes a decrease in saliva secretion. 13 During atrophy of salivary glands caused by excretory duct ligation, acinar cells disappear due to apoptosis 14,15 or dedifferentiation. 16 In this study, atrophy of acinar cells and inflammatory cell infiltration were observed on the ligated side.…”

The Role of Autophagy in Salivary Gland Homeostasis and Stress Responses

“…Studies using animal models of duct ligation as a model of atrophy regulation have proposed that these findings could extend to obstructive sialadenitis, Sjogrën syndrome, or patients receiving head and neck radiation therapy (Silver et al 2010;Lin et al 2014). Autophagy as well as mTOR pathways were both activated in salivary glands as early as 1 d following sustained duct ligation, and thus, both pathways are implicated in salivary gland atrophy and survival, albeit possibly targeting a different population of cells (Silver et al 2010). Furthermore, daily postligation treatments of the mTOR inhibitor rapamycin delayed ligation-induced salivary gland atrophy in mice (Bozorgi et al 2014).…”