Defects in mitochondrial localization and ATP synthesis in the mdx mouse model of duchenne muscular dystrophy are not alleviated by PDE5 inhibition

Justin Percival, Michael P. Siegel, Gary Knowels, David J. Marcinek

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

Given the crucial roles for mitochondria in ATP energy supply, Ca2+ handling and cell death, mitochondrial dysfunction has long been suspected to be an important pathogenic feature in Duchenne muscular dystrophy (DMD). Despite this foresight, mitochondrial function in dystrophin-deficient muscles has remained poorly defined and unknown in vivo. Here, we used the mdx mouse model of DMD and non-invasive spectroscopy to determine the impact of dystrophin-deficiency on skeletal muscle mitochondrial localization and oxidative phosphorylation function in vivo. Mdx mitochondria exhibited significant uncoupling of oxidative phosphorylation (reduced P/O) and a reduction in maximal ATP synthesis capacity that together decreased intramuscular ATP levels. Uncoupling was not driven by increased UCP3 or ANT1 expression. Dystrophin was required to maintain subsarcolemmal mitochondria (SSM) pool density, implicating it in the spatial control of mitochondrial localization. Given that nitric oxide-cGMP pathways regulate mitochondria and that sildenafil-mediated phosphodiesterase 5 inhibition ameliorates dystrophic pathology, we tested whether sildenafil's benefits result from decreased mitochondrial dysfunction in mdx mice. Unexpectedly, sildenafil treatment did not affect mitochondrial content or oxidative phosphorylation defects in mdx mice. Rather, PDE5 inhibition decreased resting levels of ATP, phosphocreatine and myoglobin, suggesting that sildenafil improves dystrophic pathology through other mechanisms. Overall, these data indicate that dystrophin-deficiency disrupts SSM localization, promotes mitochondrial inefficiency and restricts maximal mitochondrial ATP-generating capacity. Together these defects decrease intramuscular ATP and the ability of mdx muscle mitochondria to meet ATP demand. These findings further understanding of how mitochondrial bioenergetic dysfunction contributes to disease pathogenesis in dystrophin-deficient skeletal muscle in vivo.

Original languageEnglish
Article numberdds415
Pages (from-to)153-167
Number of pages15
JournalHuman Molecular Genetics
Volume22
Issue number1
DOIs
StatePublished - Jan 1 2013

Fingerprint

Inbred mdx Mouse
Duchenne Muscular Dystrophy
Dystrophin
Adenosine Triphosphate
Mitochondria
Oxidative Phosphorylation
Skeletal Muscle
Type 5 Cyclic Nucleotide Phosphodiesterases
Pathology
Muscle Mitochondrion
Phosphocreatine
Myoglobin
Energy Metabolism
Spectrum Analysis
Nitric Oxide
Cell Death
Muscles
Sildenafil Citrate

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Defects in mitochondrial localization and ATP synthesis in the mdx mouse model of duchenne muscular dystrophy are not alleviated by PDE5 inhibition. / Percival, Justin; Siegel, Michael P.; Knowels, Gary; Marcinek, David J.

In: Human Molecular Genetics, Vol. 22, No. 1, dds415, 01.01.2013, p. 153-167.

Research output: Contribution to journalArticle

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