title: Impaired Muscle Mitochondrial Biogenesis and Myogenesis in Spinal Muscular Atrophy.
abstract: OBJECTIVE
  The important depletion of mitochondrial DNA (mtDNA) and the general depression of mitochondrial respiratory chain complex levels (including complex II) have been confirmed, implying an increasing paucity of mitochondria in the muscle from patients with types I, II, and III spinal muscular atrophy (SMA-I, -II, and -III, respectively).
  
  
  OBJECTIVE
  To investigate mitochondrial dysfunction in a large series of muscle biopsy samples from patients with SMA.
  
  
  METHODS
  We studied quadriceps muscle samples from 24 patients with genetically documented SMA and paraspinal muscle samples from 3 patients with SMA-II undergoing surgery for scoliosis correction. Postmortem muscle samples were obtained from 1 additional patient. Age-matched controls consisted of muscle biopsy specimens from healthy children aged 1 to 3 years who had undergone analysis for suspected myopathy. Analyses were performed at the Neuromuscular Unit, Istituto di Ricovero e Cura a Carattere Scientifico Foundation Ca' Granda Ospedale Maggiore Policlinico-Milano, from April 2011 through January 2015.
  
  
  METHODS
  We used histochemical, biochemical, and molecular techniques to examine the muscle samples.
  
  
  METHODS
  Respiratory chain activity and mitochondrial content.
  
  
  RESULTS
  Results of histochemical analysis revealed that cytochrome-c oxidase (COX) deficiency was more evident in muscle samples from patients with SMA-I and SMA-II. Residual activities for complexes I, II, and IV in muscles from patients with SMA-I were 41%, 27%, and 30%, respectively, compared with control samples (P < .005). Muscle mtDNA content and cytrate synthase activity were also reduced in all 3 SMA types (P < .05). We linked these alterations to downregulation of peroxisome proliferator-activated receptor coactivator 1α, the transcriptional activators nuclear respiratory factor 1 and nuclear respiratory factor 2, mitochondrial transcription factor A, and their downstream targets, implying depression of the entire mitochondrial biogenesis. Results of Western blot analysis confirmed the reduced levels of the respiratory chain subunits that included mitochondrially encoded COX1 (47.5%; P = .004), COX2 (32.4%; P < .001), COX4 (26.6%; P < .001), and succinate dehydrogenase complex subunit A (65.8%; P = .03) as well as the structural outer membrane mitochondrial porin (33.1%; P < .001). Conversely, the levels of expression of 3 myogenic regulatory factors-muscle-specific myogenic factor 5, myoblast determination 1, and myogenin-were higher in muscles from patients with SMA compared with muscles from age-matched controls (P < .05).
  
  
  CONCLUSIONS
  Our results strongly support the conclusion that an altered regulation of myogenesis and a downregulated mitochondrial biogenesis contribute to pathologic change in the muscle of patients with SMA. Therapeutic strategies should aim at counteracting these changes.
authors.affiliation: Neuromuscular Unit, Dino Ferrari Centre, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Foundation Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Ripolone
authors.affiliation: Neurology Unit, Neuroscience Section, Department of Pathophysiology and Transplantation, Dino Ferrari Centre, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: Ronchi
authors.affiliation: Neuromuscular Unit, Dino Ferrari Centre, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Foundation Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Violano
authors.affiliation: Sien-Servicios Integrales en Neurologia, Universidad de Antioquia, Medellin, Colombia.
authors.forename: Dionis
authors.initials: D
authors.lastname: Vallejo
authors.affiliation: Neuromuscular Unit, Dino Ferrari Centre, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Foundation Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy.
authors.forename: Gigliola
authors.initials: G
authors.lastname: Fagiolari
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, New York.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Barca
authors.affiliation: Neuromuscular Unit, Dino Ferrari Centre, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Foundation Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Lucchini
authors.affiliation: Neuromuscular Unit, Dino Ferrari Centre, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Foundation Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Colombo
authors.affiliation: Neuromuscular Unit, Dino Ferrari Centre, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Foundation Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Villa
authors.affiliation: Child Neuropsychiatry Unit, C. Mondino National Neurological Institute, Pavia, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Berardinelli
authors.affiliation: Child Neuropsychiatry Unit, C. Mondino National Neurological Institute, Pavia, Italy.
authors.forename: Umberto
authors.initials: U
authors.lastname: Balottin
authors.affiliation: Neuromuscular Diseases and Neuroimmunology Unit, Department of Clinical Neurosciences, IRCCS Foundation, Carlo Besta Neurological Institute, Milan, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Morandi
authors.affiliation: Neuromuscular Diseases and Neuroimmunology Unit, Department of Clinical Neurosciences, IRCCS Foundation, Carlo Besta Neurological Institute, Milan, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Mora
authors.affiliation: Neurology Unit, Neuroscience Section, Department of Pathophysiology and Transplantation, Dino Ferrari Centre, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy.
authors.forename: Andreina
authors.initials: A
authors.lastname: Bordoni
authors.affiliation: Neurology Unit, Neuroscience Section, Department of Pathophysiology and Transplantation, Dino Ferrari Centre, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Fortunato
authors.affiliation: Neurology Unit, Neuroscience Section, Department of Pathophysiology and Transplantation, Dino Ferrari Centre, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Corti
authors.affiliation: Reference Center for Rare Neuromuscular Disorders, Department of Neurosciences, University of Messina, Azienda Ospedaliera Universitaria Policlinico G. Martino, Messina, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Parisi
authors.affiliation: Reference Center for Rare Neuromuscular Disorders, Department of Neurosciences, University of Messina, Azienda Ospedaliera Universitaria Policlinico G. Martino, Messina, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Toscano
authors.affiliation: Neuromuscular Unit, Dino Ferrari Centre, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Foundation Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Sciacco
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, New York.
authors.forename: Salvatore
authors.initials: S
authors.lastname: DiMauro
authors.affiliation: Neurology Unit, Neuroscience Section, Department of Pathophysiology and Transplantation, Dino Ferrari Centre, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy.
authors.forename: Giacomo P
authors.initials: GP
authors.lastname: Comi
authors.affiliation: Neuromuscular Unit, Dino Ferrari Centre, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Foundation Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Moggio
mesh_terms: D000293:Adolescent; D002675:Child, Preschool; D004272:DNA, Mitochondrial / Q000378:metabolism*; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D024510:Muscle Development / Q000502:physiology*; D018482:Muscle, Skeletal / Q000378:metabolism*; D009134:Muscular Atrophy, Spinal / Q000378:metabolism*; D052097:Quadriceps Muscle / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial
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