title: Endoplasmic Reticulum Oxidative Stress Triggers Tgf-Beta-Dependent Muscle Dysfunction by Accelerating Ascorbic Acid Turnover.
abstract: Endoplasmic reticulum (ER) and oxidative stress are two related phenomena that have important metabolic consequences. As many skeletal muscle diseases are triggered by oxidative stress, we explored the chain of events linking a hyperoxidized ER (which causes ER and oxidative stress) with skeletal muscle dysfunction. An unbiased exon expression array showed that the combined genetic modulation of the two master ER redox proteins, selenoprotein N (SEPN1) and endoplasmic oxidoreductin 1 (ERO1), led to an SEPN1-related myopathic phenotype due to excessive signalling of transforming growth factor (TGF)-beta. The increased TGF-beta activity in the genetic mutants was caused by accelerated turnover of the ER localized (anti-oxidant) ascorbic acid that affected collagen deposition in the extracellular matrix. In a mouse mutant of SEPN1, which is dependent on exogenous ascorbic acid, a limited intake of ascorbic acid revealed a myopathic phenotype as a consequence of an altered TGF-beta signalling. Indeed, systemic antagonism of TGF-beta re-established skeletal muscle function in SEPN1 mutant mice. In conclusion, this study sheds new light on the molecular mechanism of SEPN1-related myopathies and indicates that the TGF-beta/ERO1/ascorbic acid axis offers potential for their treatment.
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Pozzer
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors.forename: Mariagrazia
authors.initials: M
authors.lastname: Favellato
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Bolis
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors.forename: Roberto William
authors.initials: RW
authors.lastname: Invernizzi
authors.affiliation: Venetian Institute of Molecular Medicine, 35100, Padua, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Solagna
authors.affiliation: Venetian Institute of Molecular Medicine, 35100, Padua, Italy.|Department of Biomedical Science, University of Padova, 35100, Padua, Italy.
authors.forename: Bert
authors.initials: B
authors.lastname: Blaauw
authors.affiliation: Dulbecco Telethon Institute at IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors.forename: Ester
authors.initials: E
authors.lastname: Zito
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D001205:Ascorbic Acid / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000502:physiology*; D020869:Gene Expression Profiling; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D006651:Histocytochemistry; D051379:Mice; D008822:Mice, Transgenic; D046228:Microarray Analysis; D008854:Microscopy, Electron; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000473:pathology / Q000503:physiopathology*; D009135:Muscular Diseases / Q000473:pathology / Q000503:physiopathology*; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D010088:Oxidoreductases; D051140:Selenoproteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D006023:Glycoproteins; D009124:Muscle Proteins; D050505:Mutant Proteins; C545253:SEPN1 protein, mouse; D051140:Selenoproteins; D016212:Transforming Growth Factor beta; C491864:Ero1l protein, mouse; D010088:Oxidoreductases; D001205:Ascorbic Acid