Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
5500998 | Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease | 2017 | 27 Pages |
Abstract
Besides its role in calcium (Ca2Â +) homeostasis, the sarco-endoplamic reticulum (SR/ER) controls protein folding and is tethered to mitochondria. Under pathophysiological conditions the unfolded protein response (UPR) is associated with disturbance in SR/ER-mitochondria crosstalk. Here, we investigated whether ER stress altered SR/ER-mitochondria links, Ca2Â + handling and muscle damage in WT (Wild Type) and mdx mice, the murine model of Duchenne Muscular Dystrophy (DMD). In WT mice, the SR/ER-mitochondria links were decreased in isolated FDB muscle fibers after injection of ER stress activator tunicamycin (TM). Ca2Â + imaging revealed an increase of cytosolic Ca2Â + transient and a decrease of mitochondrial Ca2Â + uptake. The force generating capacity of muscle dropped after TM. This impaired contractile function was accompanied by an increase in autophagy markers and calpain-1 activation. Conversely, ER stress inhibitors restored SR/ER-mitochondria links, mitochondrial Ca2Â + uptake and improved diaphragm contractility in mdx mice. Our findings demonstrated that ER stress-altered SR/ER-mitochondria links, disturbed Ca2Â + handling and muscle function in WT and mdx mice. Thus, ER stress may open up a prospect of new therapeutic targets in DMD.
Keywords
Ribosomal protein S14RPS14RPLP0tunicamycinDdit3grp75GRP78TUDCAFBSFDBDMDGlucose regulated protein 75EDLIP3RATF6LC3eIF2αeukaryotic translation initiation factor 2Aribosomal protein large P0CTLIRE1αAdenosine TriphosphateATPinositol-requiring enzyme 1flexor digitorum brevisextensor digitorum longusDuchenne muscular dystrophyactivating transcription factor 6microtubule-associated protein 1 light chain 3 alphaPERKControlglucose regulated protein 78Inositol 1,4,5-triphosphate receptor
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Authors
Marion Pauly, Claire Angebault-Prouteau, Haikel Dridi, Cécile Notarnicola, Valérie Scheuermann, Alain Lacampagne, Stefan Matecki, Jérémy Fauconnier,