title: Mitochondrial dysfunction in the skeletal muscle of a mouse model of Rett syndrome (RTT): implications for the disease phenotype.
abstract: Rett syndrome (RTT) is a severe neurodevelopmental disorder, predominantly caused by mutations in the X-linked Methyl-CpG-binding protein 2 (MECP2) gene. Patients present with numerous functional deficits including intellectual disability and abnormalities of movement. Clinical and biochemical features may overlap with those seen in patients with primary mitochondrial respiratory chain disorders. In the late stages of the disorder, patients suffer from motor deterioration and usually require assisted mobility. Using a mouse model of RTT (Mecp2(tm1Tam)), we studied the mitochondrial function in the hind-limb skeletal muscle of these mice. We identified a reduction in cytochrome c oxidase subunit I (MTCO1) at both the transcript and protein level, in accordance with our previous findings in RTT patient brain studies. Mitochondrial respiratory chain (MRC) enzyme activity of complexes II+III (COII+III) and complex IV (COIV), and glutathione (GSH) levels were significantly reduced in symptomatic mice, but not in the pre-symptomatic mice. Our findings suggest that mitochondrial abnormalities in the skeletal muscle may contribute to the progressive deterioration in mobility in RTT through the accumulation of free radicals, as evidenced by the decrease in reduced glutathione (GSH). We hypothesise that a diminution in GSH leads to an accumulation of free radicals and an increase in oxidative stress. This may impact on respiratory chain function and contribute in part to the progressive neurological and motor deterioration seen in the Mecp2-mutant mouse. Treatment strategies aimed at restoring cellular GSH levels may prove to be a novel target area to consider in future approaches to RTT therapies.
authors.affiliation: NSW Centre for Rett Syndrome Research, Western Sydney Genetics Program, Children's Hospital at Westmead, Sydney, Australia; Discipline of Paediatrics & Child Health, University of Sydney, Australia.
authors.forename: W A
authors.initials: WA
authors.lastname: Gold
authors.affiliation: NSW Centre for Rett Syndrome Research, Western Sydney Genetics Program, Children's Hospital at Westmead, Sydney, Australia.
authors.forename: S L
authors.initials: SL
authors.lastname: Williamson
authors.affiliation: NSW Centre for Rett Syndrome Research, Western Sydney Genetics Program, Children's Hospital at Westmead, Sydney, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Kaur
authors.affiliation: Neurometabolic Unit, National Hospital and Department of Molecular Neuroscience, Institute of Neurology, London, United Kingdom.
authors.forename: I P
authors.initials: IP
authors.lastname: Hargreaves
authors.affiliation: Neurometabolic Unit, National Hospital and Department of Molecular Neuroscience, Institute of Neurology, London, United Kingdom.
authors.forename: J M
authors.initials: JM
authors.lastname: Land
authors.affiliation: Embryology Unit, Children's Medical Research Institute, Sydney, Australia.
authors.forename: G J
authors.initials: GJ
authors.lastname: Pelka
authors.affiliation: Embryology Unit, Children's Medical Research Institute, Sydney, Australia; Discipline of Medicine, Sydney Medical School, University of Sydney, Australia.
authors.forename: P P L
authors.initials: PP
authors.lastname: Tam
authors.affiliation: NSW Centre for Rett Syndrome Research, Western Sydney Genetics Program, Children's Hospital at Westmead, Sydney, Australia; Discipline of Paediatrics & Child Health, University of Sydney, Australia; Discipline of Genetic Medicine, Sydney Medical School, University of Sydney, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Christodoulou
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D042963:Electron Transport Complex II / Q000032:analysis; D014450:Electron Transport Complex III / Q000032:analysis; D003576:Electron Transport Complex IV / Q000032:analysis; D005609:Free Radicals / Q000633:toxicity; D005978:Glutathione / Q000032:analysis; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism / Q000502:physiology*; D018482:Muscle, Skeletal / Q000503:physiopathology*; D018384:Oxidative Stress; D015518:Rett Syndrome / Q000503:physiopathology*
chemical_list: D005609:Free Radicals; D042963:Electron Transport Complex II; D003576:Electron Transport Complex IV; D014450:Electron Transport Complex III; D005978:Glutathione
keywords: Mitochondria; Oxidative stress; PGC-1α; Reactive oxygen species; Respiratory chain; Rett syndrome; Skeletal muscle