A maladaptive ER stress response triggers dysfunction in highly active muscles of mice with SELENON loss
Diego Pozzer,
Ersilia Varone,
Alexander Chernorudskiy,
Silvia Schiarea,
Sonia Missiroli,
Carlotta Giorgi,
Paolo Pinton,
Marta Canato,
Elena Germinario,
Leonardo Nogara,
Bert Blaauw,
Ester Zito
Affiliations
Diego Pozzer
Dulbecco Telethon Institute at Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
Ersilia Varone
Dulbecco Telethon Institute at Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
Alexander Chernorudskiy
Dulbecco Telethon Institute at Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
Silvia Schiarea
Dulbecco Telethon Institute at Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
Sonia Missiroli
Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies (LTTA), Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
Carlotta Giorgi
Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies (LTTA), Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
Paolo Pinton
Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies (LTTA), Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy; Maria Cecilia Hospital, GVM Care & Research, 48033 Cotignola, Ravenna, Italy
Marta Canato
Department of Biomedical Sciences, University of Padua, Padua, Italy
Elena Germinario
Department of Biomedical Sciences, University of Padua, Padua, Italy
Leonardo Nogara
Department of Biomedical Sciences, University of Padua, Padua, Italy; Venetian Institute of Molecular Medicine, Padua, Italy
Bert Blaauw
Department of Biomedical Sciences, University of Padua, Padua, Italy; Venetian Institute of Molecular Medicine, Padua, Italy; Correspondence to: Venetian Institute of Molecular Medicine, via Orus 2, Padua, Italy.
Ester Zito
Dulbecco Telethon Institute at Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy; Correspondence to: Istituto di Ricerche Farmacologiche Mario Negri, IRCCS, Via La Masa 19, 20156 Milano, Italy.
Selenoprotein N (SELENON) is an endoplasmic reticulum (ER) protein whose loss of function leads to human SELENON-related myopathies. SelenoN knockout (KO) mouse limb muscles, however, are protected from the disease, and display no major alterations in muscle histology or contractile properties. Interestingly, we find that the highly active diaphragm muscle shows impaired force production, in line with the human phenotype. In addition, after repeated stimulation with a protocol which induces muscle fatigue, also hind limb muscles show altered relaxation times. Mechanistically, muscle SELENON loss alters activity-dependent calcium handling selectively impinging on the Ca2+ uptake of the sarcoplasmic reticulum and elicits an ER stress response, including the expression of the maladaptive CHOP-induced ERO1. In SELENON-devoid models, ERO1 shifts ER redox to a more oxidised poise, and further affects Ca2+ uptake. Importantly, CHOP ablation in SelenoN KO mice completely prevents diaphragm dysfunction, the prolonged limb muscle relaxation after fatigue, and restores Ca2+ uptake by attenuating the induction of ERO1. These findings suggest that SELENON is part of an ER stress-dependent antioxidant response and that the CHOP/ERO1 branch of the ER stress response is a novel pathogenic mechanism underlying SELENON-related myopathies. Key words: Diaphragm dysfunction, ER stress response, SELENON