Hughes 2019 J Physiol

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Hughes MC, Ramos SV, Turnbull PC, Edgett BA, Huber JS, Polidovitch N, Schlattner U, Backx PH, Simpson JA, Perry CGR (2019) Impairments in left ventricular mitochondrial bioenergetics precede overt cardiac dysfunction and remodelling in Duchenne muscular dystrophy. J Physiol [Epub ahead of print].

» PMID: 30674086

Hughes MC, Ramos SV, Turnbull PC, Edgett BA, Huber JS, Polidovitch N, Schlattner U, Backx PH, Simpson JA, Perry CGR (2019) J Physiol

Abstract: In Duchenne muscular dystrophy (DMD), mitochondrial dysfunction is predicted as a response to numerous cellular stressors yet the degree and contribution of mitochondria to the onset of cardiomyopathy remains unknown. To resolve this uncertainty, we designed in vitro assessments of mitochondrial bioenergetics to model mitochondrial control parameters that influence cardiac function. Both left ventricular mitochondrial responsiveness to the central bioenergetic controller ADP as well as the ability of creatine to facilitate mitochondrial-cytoplasmic phosphate shuttling were assessed. These measurements were performed in D2.B10-DMDmdx/2J mice - a model that demonstrates skeletal muscle atrophy and weakness due to limited regenerative capacities and cardiomyopathy more akin to people with DMD than classic models. At 4 weeks of age, there was no evidence of cardiac remodelling or cardiac dysfunction despite impairments in ADP-stimulated respiration and ADP- attenuation of H2O2 emission. These impairments were seen at both sub-maximal and maximal ADP concentrations despite no reductions in mitochondrial content markers. The ability of creatine to enhance ADP's control of mitochondrial bioenergetics was also impaired, suggesting an impairment in mitochondrial creatine kinase-dependent phosphate shuttling. Susceptibly to permeability transition pore opening and the subsequent activation of cell death pathways remained unchanged. Mitochondrial H2O2 emission was elevated despite no change in markers of irreversible oxidative damage, suggesting alternative redox signalling mechanisms should be explored. These findings demonstrate that selective mitochondrial dysfunction precedes the onset of overt cardiomyopathy in D2.mdx mice, suggesting that improving mitochondrial bioenergetics by restoring ADP, creatine-dependent phosphate shuttling and Complex I should be considered for treating DMD patients.

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Keywords: Duchenne muscular dystrophy, Cardiomyopathy, Mitochondria, Reactive oxygen species, Respiration Bioblast editor: Plangger M O2k-Network Lab: CA Toronto Perry CG, FR Grenoble Schlattner U


Labels: MiParea: Respiration  Pathology: Myopathy 

Organism: Mouse  Tissue;cell: Heart  Preparation: Permeabilized tissue 

Regulation: Calcium  Coupling state: LEAK, OXPHOS  Pathway: N, NS  HRR: Oxygraph-2k 

2019-01