title: Misregulation of calcium-handling proteins promotes hyperactivation of calcineurin-NFAT signaling in skeletal muscle of DM1 mice.
abstract: Myotonic Dystrophy type 1 (DM1) is caused by an expansion of CUG repeats in DMPK mRNAs. This mutation affects alternative splicing through misregulation of RNA-binding proteins. Amongst pre-mRNAs that are mis-spliced, several code for proteins involved in calcium homeostasis suggesting that calcium-handling and signaling are perturbed in DM1. Here, we analyzed expression of such proteins in DM1 mouse muscle. We found that the levels of several sarcoplasmic reticulum proteins (SERCA1, sarcolipin and calsequestrin) are altered, likely contributing to an imbalance in calcium homeostasis. We also observed that calcineurin (CnA) signaling is hyperactivated in DM1 muscle. Indeed, CnA expression and phosphatase activity are both markedly increased in DM1 muscle. Coherent with this, we found that activators of the CnA pathway (MLP, FHL1) are also elevated. Consequently, NFATc1 expression is increased in DM1 muscle and becomes relocalized to myonuclei, together with an up-regulation of its transcriptional targets (RCAN1.4 and myoglobin). Accordingly, DM1 mouse muscles display an increase in oxidative metabolism and fiber hypertrophy. To determine the functional consequences of this CnA hyperactivation, we administered cyclosporine A, an inhibitor of CnA, to DM1 mice. Muscles of treated DM1 mice showed an increase in CUGBP1 levels, and an exacerbation of key alternative splicing events associated with DM1. Finally, inhibition of CnA in cultured human DM1 myoblasts also resulted in a splicing exacerbation of the insulin receptor. Together, these findings show for the first time that calcium-CnA signaling is hyperactivated in DM1 muscle and that such hyperactivation represents a beneficial compensatory adaptation to the disease.
authors.affiliation: Department of Cellular and Molecular Medicine and Center for Neuromuscular Disease, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Aymeric
authors.initials: A
authors.lastname: Ravel-Chapuis
authors.affiliation: Department of Cellular and Molecular Medicine and Center for Neuromuscular Disease, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Guy
authors.initials: G
authors.lastname: Bélanger
authors.affiliation: Department of Cellular and Molecular Medicine and Center for Neuromuscular Disease, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Côté
authors.affiliation: Department of Exercise Science, Faculty of Arts and Science, Concordia University, Montreal, QC, Canada.
authors.forename: Robin N
authors.initials: RN
authors.lastname: Michel
authors.affiliation: Department of Cellular and Molecular Medicine and Center for Neuromuscular Disease, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Bernard J
authors.initials: BJ
authors.lastname: Jasmin
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D015703:Antigens, CD; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D018929:Cell Culture Techniques; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism; D032446:Myoblasts / Q000378:metabolism; D009223:Myotonic Dystrophy / Q000235:genetics* / Q000378:metabolism; D065636:Myotonin-Protein Kinase / Q000235:genetics* / Q000378:metabolism; D050778:NFATC Transcription Factors; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics; D016601:RNA-Binding Proteins; D011972:Receptor, Insulin; D012519:Sarcoplasmic Reticulum / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D015703:Antigens, CD; C585516:DMPK protein, mouse; D050778:NFATC Transcription Factors; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C435941:INSR protein, human; D011972:Receptor, Insulin; D065636:Myotonin-Protein Kinase; D019703:Calcineurin; D002118:Calcium