title: Inositol 1,4,5-trisphosphate (IP3)-dependent Ca2+ signaling mediates delayed myogenesis in Duchenne muscular dystrophy fetal muscle.
abstract: Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disorder characterized by muscle wasting and premature death. The defective gene is dystrophin, a structural protein, absence of which causes membrane fragility and myofiber necrosis. Several lines of evidence showed that in adult DMD patients dystrophin is involved in signaling pathways that regulate calcium homeostasis and differentiation programs. However, secondary aspects of the disease, such as inflammation and fibrosis development, might represent a bias in the analysis. Because fetal muscle is not influenced by gravity and does not suffer from mechanical load and/or inflammation, we investigated 12-week-old fetal DMD skeletal muscles, highlighting for the first time early alterations in signaling pathways mediated by the absence of dystrophin itself. We found that PLC/IP3/IP3R/Ryr1/Ca(2+) signaling is widely active in fetal DMD skeletal muscles and, through the calcium-dependent PKCα protein, exerts a fundamental regulatory role in delaying myogenesis and in myofiber commitment. These data provide new insights into the origin of DMD pathology during muscle development.
authors.affiliation: Laboratorio di Cellule Staminali, Dipartimento di Fisiopatologia medico-chirurgica e dei Trapianti, Università degli Studi di Milano, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milano, Centro Dino Ferrari, Via Francesco Sforza 35, Milan 20122, Centro Dino Ferrari, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Farini
authors.affiliation: Laboratorio di Cellule Staminali, Dipartimento di Fisiopatologia medico-chirurgica e dei Trapianti, Università degli Studi di Milano, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milano, Centro Dino Ferrari, Via Francesco Sforza 35, Milan 20122, Centro Dino Ferrari, Italy.
authors.forename: Clementina
authors.initials: C
authors.lastname: Sitzia
authors.affiliation: Laboratorio di Cellule Staminali, Dipartimento di Fisiopatologia medico-chirurgica e dei Trapianti, Università degli Studi di Milano, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milano, Centro Dino Ferrari, Via Francesco Sforza 35, Milan 20122, Centro Dino Ferrari, Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Cassinelli
authors.affiliation: Laboratorio di Cellule Staminali, Dipartimento di Fisiopatologia medico-chirurgica e dei Trapianti, Università degli Studi di Milano, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milano, Centro Dino Ferrari, Via Francesco Sforza 35, Milan 20122, Centro Dino Ferrari, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Colleoni
authors.affiliation: Laboratorio di Cellule Staminali, Dipartimento di Fisiopatologia medico-chirurgica e dei Trapianti, Università degli Studi di Milano, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milano, Centro Dino Ferrari, Via Francesco Sforza 35, Milan 20122, Centro Dino Ferrari, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Parolini
authors.affiliation: Consiglio Nazionale delle Ricerche, Istituto per lo Studio delle Macromolecole (CNR-ISMAC), via Bassini 15, Milano 20133, Italy.
authors.forename: Umberto
authors.initials: U
authors.lastname: Giovanella
authors.affiliation: Laboratorio di Cellule Staminali, Dipartimento di Fisiopatologia medico-chirurgica e dei Trapianti, Università degli Studi di Milano, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milano, Centro Dino Ferrari, Via Francesco Sforza 35, Milan 20122, Centro Dino Ferrari, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Maciotta
authors.affiliation: Servizio 'Legge 194' Dipartimento BDN-Fondazione IRCCS, Policlinico Mangiagalli-Regina Elena, Via Francesco Sforza 35, Milan 20122, Italy.
authors.forename: Augusto
authors.initials: A
authors.lastname: Colombo
authors.affiliation: Laboratorio di Cellule Staminali, Dipartimento di Fisiopatologia medico-chirurgica e dei Trapianti, Università degli Studi di Milano, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milano, Centro Dino Ferrari, Via Francesco Sforza 35, Milan 20122, Centro Dino Ferrari, Italy.
authors.forename: Mirella
authors.initials: M
authors.lastname: Meregalli
authors.affiliation: Laboratorio di Cellule Staminali, Dipartimento di Fisiopatologia medico-chirurgica e dei Trapianti, Università degli Studi di Milano, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milano, Centro Dino Ferrari, Via Francesco Sforza 35, Milan 20122, Centro Dino Ferrari, Italy yvan.torrente@unimi.it.
authors.forename: Yvan
authors.initials: Y
authors.lastname: Torrente
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001706:Biopsy; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling; D005333:Fetus / Q000378:metabolism* / Q000473:pathology; D018507:Gene Expression Regulation, Developmental; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D008954:Models, Biological; D024510:Muscle Development; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000196:embryology* / Q000378:metabolism / Q000473:pathology; D009137:Muscular Dystrophy, Animal / Q000378:metabolism / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000196:embryology* / Q000378:metabolism* / Q000473:pathology; D051763:PAX7 Transcription Factor / Q000378:metabolism; D051571:Protein Kinase C-alpha / Q000378:metabolism
chemical_list: D015415:Biomarkers; D015220:Calcium Channels; D051763:PAX7 Transcription Factor; C497321:PAX7 protein, human; D015544:Inositol 1,4,5-Trisphosphate; D051571:Protein Kinase C-alpha; D002118:Calcium
keywords: Calcium channels; DMD fetus; Dystrophin signaling; IP3/IP3R pathway; Myosin isoforms