Murdoch University Research Repository

Welcome to the Murdoch University Research Repository

The Murdoch University Research Repository is an open access digital collection of research
created by Murdoch University staff, researchers and postgraduate students.

Learn more

Treatment of Adult mdx Mice with Phosphorodiamidate Morpholino Oligomer Restores Cardiac Mitochondrial Energetics and Prevents the Dystrophic Cardiomyopathy

Viola, H.M., Johnstone, V.P.A., Adams, A.M., Fletcher, S. and Hool, L.C. (2017) Treatment of Adult mdx Mice with Phosphorodiamidate Morpholino Oligomer Restores Cardiac Mitochondrial Energetics and Prevents the Dystrophic Cardiomyopathy. Biophysical Journal, 112 (3). 245a.

Link to Published Version:
*Subscription may be required


Duchenne muscular dystrophy (DMD) occurs due to the absence of dystrophin, and is associated with a fatal dilated cardiomyopathy. DMD-associated cardiomyopathy is underpinned by disrupted cytoskeletal architecture and poor energy metabolism. The L-type Ca2+ channel (LTCC) plays a critical role facilitating Ca2+ influx required for contraction, but also regulates mitochondrial function. This crosstalk is mediated via the cytoskeleton, and is disrupted in a mouse model of DMD (mdx). We previously demonstrated that treatment of pre-cardiomyopathic mdx mice with 10mg/kg/wk phosphorodiamidate morpholino oligomer (PMO) to induce skipping of exon 23 (M23D) for 24wks partially restored increases in mitochondrial membrane potential (Ψm) and metabolic activity in response to activation of LTCC in myocytes isolated from pre-cardiomyopathic mice. Here we investigated the effect of a short-term, but high PMO treatment dose, namely 120mg/kg/wk for 3wks, on alterations in Ψm and metabolic activity. Treatment resulted in partial restoration of Ψm and metabolic activity. Based on these findings we investigated whether a long-term and high PMO treatment dose would more effectively restore Ψm and metabolic activity to wt levels. 24wk old pre-cardiomyopathic mdx mice were treated with 120mg/kg/wk for 19wks. Positive exon skipping was verified via RT-PCR, and immunohistochemistry confirmed the presence of dystrophin positive fibers within mdx heart tissue. PMO treatment completely restored Ψm to wt levels (wt untreated: 30.9±4.2%, n=11; mdx untreated: 1.6±0.8%, n=8; mdx treated: 31.6±2.6%, n=7). PMO treatment also completely restored metabolic activity (assessed as formation of formazan from tetrazolium salt) (wt untreated: 48.9±6.4%, n=15; mdx untreated: 3.0±1.3%, n=11; mdx treated: 64.9±14.0%, n=26). Furthermore, PMO treatment prevented development of the mdx cardiomyopathy assessed using serial echocardiography. These data indicate that treatment with M23D restores cardiac mitochondrial energetics in adult mdx mice. We propose that restoring mitochondrial function may play a vital role in mediating PMO-induced improvements in contractility.

Item Type: Journal Article
Murdoch Affiliation(s): Centre for Comparative Genomics
Publisher: Elsevier Inc
Copyright: © Elsevier B.V.
Item Control Page Item Control Page