title: MTOR-independent induction of autophagy in trabecular meshwork cells subjected to biaxial stretch.
abstract: The trabecular meshwork (TM) is part of a complex tissue that controls the exit of aqueous humor from the anterior chamber of the eye, and therefore helps maintaining intraocular pressure (IOP). Because of variations in IOP with changing pressure gradients and fluid movement, the TM and its contained cells undergo morphological deformations, resulting in distention and stretching. It is therefore essential for TM cells to continuously detect and respond to these mechanical forces and adapt their physiology to maintain proper cellular function and protect against mechanical injury. Here we demonstrate the activation of autophagy, a pro-survival pathway responsible for the degradation of long-lived proteins and organelles, in TM cells when subjected to biaxial static stretch (20% elongation), as well as in high-pressure perfused eyes (30mmHg). Morphological and biochemical markers for autophagy found in the stretched cells include elevated LC3-II levels, increased autophagic flux, and the presence of autophagic figures in electron micrographs. Furthermore, our results indicate that the stretch-induced autophagy in TM cells occurs in an MTOR- and BAG3-independent manner. We hypothesize that activation of autophagy is part of the physiological response that allows TM cells to cope and adapt to mechanical forces.
authors.affiliation: Duke University, Department of Ophthalmology, Durham, NC, USA.
authors.forename: Kristine M
authors.initials: KM
authors.lastname: Porter
authors.affiliation: Duke University, Department of Ophthalmology, Durham, NC, USA.
authors.forename: Nallathambi
authors.initials: N
authors.lastname: Jeyabalan
authors.affiliation: Duke University, Department of Ophthalmology, Durham, NC, USA. Electronic address: paloma.liton@dm.duke.edu.
authors.forename: Paloma B
authors.initials: PB
authors.lastname: Liton
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D001343:Autophagy; D015153:Blotting, Western; D002478:Cells, Cultured; D006801:Humans; D007429:Intraocular Pressure; D008247:Lysosomes; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009924:Organ Culture Techniques; D034741:RNA, Small Interfering / Q000235:genetics; D013314:Stress, Mechanical; D013552:Swine; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014129:Trabecular Meshwork / Q000378:metabolism / Q000473:pathology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C414431:BAG3 protein, human; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: Autophagy; Chaperon-assisted autophagy; Glaucoma; MTOR pathway; Mechanical stress; Trabecular meshwork