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Redox state and mitochondrial respiratory chain function in skeletal muscle of LGMD2A patients.
Nilsson, Mats I; Macneil, Lauren G; Kitaoka, Yu; Alqarni, Fatimah; Suri, Rahul; Akhtar, Mahmood; Haikalis, Maria E; Dhaliwal, Pavneet; Saeed, Munim; Tarnopolsky, Mark A.
Afiliación
  • Nilsson MI; Department of Pediatrics and Medicine, Neuromuscular Clinic, McMaster University Hospital, Hamilton, Ontario, Canada.
  • Macneil LG; Department of Pediatrics and Medicine, Neuromuscular Clinic, McMaster University Hospital, Hamilton, Ontario, Canada.
  • Kitaoka Y; Department of Pediatrics and Medicine, Neuromuscular Clinic, McMaster University Hospital, Hamilton, Ontario, Canada.
  • Alqarni F; Department of Pediatrics and Medicine, Neuromuscular Clinic, McMaster University Hospital, Hamilton, Ontario, Canada.
  • Suri R; Department of Pediatrics and Medicine, Neuromuscular Clinic, McMaster University Hospital, Hamilton, Ontario, Canada.
  • Akhtar M; Department of Pediatrics and Medicine, Neuromuscular Clinic, McMaster University Hospital, Hamilton, Ontario, Canada.
  • Haikalis ME; Department of Pediatrics and Medicine, Neuromuscular Clinic, McMaster University Hospital, Hamilton, Ontario, Canada.
  • Dhaliwal P; Department of Pediatrics and Medicine, Neuromuscular Clinic, McMaster University Hospital, Hamilton, Ontario, Canada.
  • Saeed M; Department of Pediatrics and Medicine, Neuromuscular Clinic, McMaster University Hospital, Hamilton, Ontario, Canada.
  • Tarnopolsky MA; Department of Pediatrics and Medicine, Neuromuscular Clinic, McMaster University Hospital, Hamilton, Ontario, Canada.
PLoS One ; 9(7): e102549, 2014.
Article en En | MEDLINE | ID: mdl-25079074
BACKGROUND: Calpain-3 deficiency causes oxidative and nitrosative stress-induced damage in skeletal muscle of LGMD2A patients, but mitochondrial respiratory chain function and anti-oxidant levels have not been systematically assessed in this clinical population previously. METHODS: We identified 14 patients with phenotypes consistent with LGMD2A and performed CAPN3 gene sequencing, CAPN3 expression/autolysis measurements, and in silico predictions of pathogenicity. Oxidative damage, anti-oxidant capacity, and mitochondrial enzyme activities were determined in a subset of muscle biopsies. RESULTS: Twenty-one disease-causing variants were detected along the entire CAPN3 gene, five of which were novel (c.338 T>C, c.500 T>C, c.1525-1 G>T, c.2115+4 T>G, c.2366 T>A). Protein- and mRNA-based tests confirmed in silico predictions and the clinical diagnosis in 75% of patients. Reductions in antioxidant defense mechanisms (SOD-1 and NRF-2, but not SOD-2), coupled with increased lipid peroxidation and protein ubiquitination, were observed in calpain-3 deficient muscle, indicating a redox imbalance primarily affecting non-mitochondrial compartments. Although ATP synthase levels were significantly lower in LGMD2A patients, citrate synthase, cytochrome c oxidase, and complex I+III activities were not different from controls. CONCLUSIONS: Despite significant oxidative damage and redox imbalance in cytosolic/myofibrillar compartments, mitochondrial respiratory chain function is largely maintained in skeletal muscle of LGMD2A patients.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Músculo Esquelético / Distrofia Muscular de Cinturas / Transporte de Electrón / Mitocondrias Límite: Female / Humans / Male Idioma: En Revista: PLoS One Asunto de la revista: CIENCIA / MEDICINA Año: 2014 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Músculo Esquelético / Distrofia Muscular de Cinturas / Transporte de Electrón / Mitocondrias Límite: Female / Humans / Male Idioma: En Revista: PLoS One Asunto de la revista: CIENCIA / MEDICINA Año: 2014 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Estados Unidos