Impairments in left ventricular mitochondrial bioenergetics precede overt cardiac dysfunction and remodelling in Duchenne muscular dystrophy

Meghan C. Hughes, Sofhia V. Ramos, Patrick C. Turnbull, Brittany A. Edgett, Jason S. Huber, Nazari Polidovitch, Uwe Schlattner, Peter H. Backx, Jeremy A. Simpson, Christopher G.R. Perry

Résultat de recherche: Articleexamen par les pairs

33 Citations (Scopus)

Résumé

Key points: Ninety-eight per cent of patients with Duchenne muscular dystrophy (DMD) develop cardiomyopathy, with 40% developing heart failure. While increased propensity for mitochondrial induction of cell death has been observed in left ventricle, it remains unknown whether this is linked to impaired mitochondrial respiratory control and elevated H2O2 emission prior to the onset of cardiomyopathy. Classic mouse models of DMD demonstrate hyper-regeneration in skeletal muscle which may mask mitochondrial abnormalities. Using a model with less regenerative capacity that is more akin to DMD patients, we observed elevated left ventricular mitochondrial H2O2 and impaired oxidative phosphorylation in the absence of cardiac remodelling or overt cardiac dysfunction at 4 weeks. These impairments were associated with dysfunctions at complex I, governance by ADP and creatine-dependent phosphate shuttling, which results in a less efficient response to energy demands. Mitochondria may be a therapeutic target for the treatment of cardiomyopathy in DMD. Abstract: In Duchenne muscular dystrophy (DMD), mitochondrial dysfunction is predicted as a response to numerous cellular stressors, yet the 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 and 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 submaximal 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.

Langue d'origineEnglish
Pages (de-à)1377-1392
Nombre de pages16
JournalJournal of Physiology
Volume598
Numéro de publication7
DOI
Statut de publicationPublished - avr. 1 2020

Note bibliographique

Funding Information:
Funding was provided to C.G.R.P. by the National Science and Engineering Research Council (NSERC no. 436138-2013) with infrastructure supported by Canada Foundation for Innovation, the Ontario Research Fund, NSERC Research Tools and Instruments, and the James H. Cummings Foundation. J.A.S was supported by the Heart and Stroke Foundation of Canada (HSFC; S13 SI 0592) and is also a new investigator with Heart and Stroke Foundation of Canada. P.B. was supported by Canadian Institutes of Health Research, Project Grant (PJT 153159) and a Canada Research Chair in Cardiovascular Biology. M.C.H. and P.C.T. were supported by a NSERC CGS-PhD scholarship. S.V.R. was supported by an Ontario Graduate Scholarship.

Funding Information:
Funding was provided to C.G.R.P. by the National Science and Engineering Research Council (NSERC no. 436138-2013) with infrastructure supported by Canada Foundation for Innovation, the Ontario Research Fund, NSERC Research Tools and Instruments, and the James H. Cummings Foundation. J.A.S was supported by the Heart and Stroke Foundation of Canada (HSFC; S13 SI 0592) and is also a new investigator with Heart and Stroke Foundation of Canada. P.B. was supported by Canadian Institutes of Health Research, Project Grant (PJT 153159) and a Canada Research Chair in Cardiovascular Biology. M.C.H. and P.C.T. were supported by a NSERC CGS-PhD scholarship. S.V.R. was supported by an Ontario Graduate Scholarship. There are no competing interests or conflicts of interest. M.H., S.V.R., P.B., J.S. and C.G.R.P. contributed to the conception or design of the work. M.H., S.V.R., P.C.T., N.P., B.E., J.H., U.S., P.B., J.S. and C.G.R.P. contributed to acquisition, analysis or interpretation of data. All authors contributed to drafting the work or revising it critically for important intellectual content. All authors approved the final version of the manuscript, agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved and all persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. Funding was provided to C.G.R.P. by the National Science and Engineering Research Council (NSERC no. 436138-2013) with infrastructure supported by Canada Foundation for Innovation, the Ontario Research Fund, NSERC Research Tools and Instruments, and the James H. Cummings Foundation. J.A.S was supported by the Heart and Stroke Foundation of Canada (HSFC; S13 SI 0592) and is also a new investigator with Heart and Stroke Foundation of Canada. P.B. was supported by Canadian Institutes of Health Research, Project Grant (PJT 153159) and a Canada Research Chair in Cardiovascular Biology. M.C.H. and P.C.T. were supported by a NSERC CGS-PhD scholarship. S.V.R. was supported by an Ontario Graduate Scholarship. We thank Dr Robert Tsushima, York University, for kindly providing access to the Vevo 2100 system.

Publisher Copyright:
© 2019 The Authors. The Journal of Physiology © 2019 The Physiological Society

ASJC Scopus Subject Areas

  • Physiology

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't

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