title: Monoamine oxidase inhibition prevents mitochondrial dysfunction and apoptosis in myoblasts from patients with collagen VI myopathies.
abstract: Although mitochondrial dysfunction and oxidative stress have been proposed to play a crucial role in several types of muscular dystrophy (MD), whether a causal link between these two alterations exists remains an open question. We have documented that mitochondrial dysfunction through opening of the permeability transition pore plays a key role in myoblasts from patients as well as in mouse models of MD, and that oxidative stress caused by monoamine oxidases (MAO) is involved in myofiber damage. In the present study we have tested whether MAO-dependent oxidative stress is a causal determinant of mitochondrial dysfunction and apoptosis in myoblasts from patients affected by collagen VI myopathies. We find that upon incubation with hydrogen peroxide or the MAO substrate tyramine myoblasts from patients upregulate MAO-B expression and display a significant rise in reactive oxygen species (ROS) levels, with concomitant mitochondrial depolarization. MAO inhibition by pargyline significantly reduced both ROS accumulation and mitochondrial dysfunction, and normalized the increased incidence of apoptosis in myoblasts from patients. Thus, MAO-dependent oxidative stress is causally related to mitochondrial dysfunction and cell death in myoblasts from patients affected by collagen VI myopathies, and inhibition of MAO should be explored as a potential treatment for these diseases.
authors.affiliation: Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Sorato
authors.affiliation: Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Menazza
authors.affiliation: Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Zulian
authors.affiliation: Institute of Molecular Genetics, National Research Council of Italy, 40136 Bologna, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Sabatelli
authors.affiliation: Department of Medical Science, Section of Medical Genetics, University of Ferrara, 44100 Ferrara, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Gualandi
authors.affiliation: Laboratory of Musculoskeletal Cell Biology, Istituto Ortopedico Rizzoli, IRCCS, 40136 Bologna, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Merlini
authors.affiliation: Department of Molecular Medicine, University of Padova, 35131 Padova, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Bonaldo
authors.affiliation: Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Canton
authors.affiliation: Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy; Neuroscience Institute, National Research Council of Italy, 35131 Padova, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Bernardi
authors.affiliation: Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy; Neuroscience Institute, National Research Council of Italy, 35131 Padova, Italy. Electronic address: dilisa@bio.unipd.it.
authors.forename: F
authors.initials: F
authors.lastname: Di Lisa
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D024142:Collagen Type VI / Q000235:genetics; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008928:Mitochondria / Q000473:pathology*; D008995:Monoamine Oxidase / Q000096:biosynthesis* / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D009136:Muscular Dystrophies / Q000201:enzymology; D032446:Myoblasts / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D018384:Oxidative Stress / Q000187:drug effects; D010293:Pargyline / Q000494:pharmacology; D014439:Tyramine / Q000494:pharmacology
chemical_list: D024142:Collagen Type VI; D008996:Monoamine Oxidase Inhibitors; D010293:Pargyline; D006861:Hydrogen Peroxide; D008995:Monoamine Oxidase; D014439:Tyramine
keywords: Cell death; Mitochondria; Monoamine oxidases; Muscular dystrophy; Oxidative stress