Dystrophic cardiomyopathy: amplification of cellular damage by Ca2+ signalling and reactive oxygen species-generating pathways

Jung, Carole; Martins, Adriano S.; Niggli, Ernst; Shirokova, Natalia

doi:10.1093/cvr/cvm089

Cited by 124 publications

(162 citation statements)

References 35 publications

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“…Because I Ca-L initiates contraction in the beating heart, we propose that altered communication between I Ca-L and the mitochondria contributes to poor metabolic activity in the mdx contracting heart demonstrated as a decrease in fractional shortening on echocardiography (Table S5). Although cytosolic and mitochondrial calcium are increased in the mdx myocyte (12,32,33), we propose that altered regulation of VDAC by I Ca-L may contribute to the poor metabolic activity.…”

Section: Discussionmentioning

confidence: 80%

Impaired functional communication between the L-type calcium channel and mitochondria contributes to metabolic inhibition in the mdx heart

Viola

Adams

Davies

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Duchenne muscular dystrophy is a fatal X-linked disease characterized by the absence of dystrophin. Approximately 20% of boys will die of dilated cardiomyopathy that is associated with cytoskeletal protein disarray, contractile dysfunction, and reduced energy production. However, the mechanisms for altered energy metabolism are not yet fully clarified. Calcium influx through the L-type Ca 2+ channel is critical for maintaining cardiac excitation and contraction. The L-type Ca 2+ channel also regulates mitochondrial function and metabolic activity via transmission of movement of the auxiliary beta subunit through intermediate filament proteins. Here, we find that activation of the L-type Ca 2+ channel is unable to induce increases in mitochondrial membrane potential and metabolic activity in intact cardiac myocytes from the murine model of Duchenne muscular dystrophy (mdx) despite robust increases recorded in wt myocytes. Treatment of mdx mice with morpholino oligomers to induce exon skipping of dystrophin exon 23 (that results in functional dystrophin accumulation) or application of a peptide that resulted in block of voltage-dependent anion channel (VDAC) "rescued" mitochondrial membrane potential and metabolic activity in mdx myocytes. The mitochondrial VDAC coimmunoprecipitated with the L-type Ca 2+ channel. We conclude that the absence of dystrophin in the mdx ventricular myocyte leads to impaired functional communication between the L-type Ca 2+ channel and mitochondrial VDAC. This appears to contribute to metabolic inhibition. These findings provide new mechanistic and functional insight into cardiomyopathy associated with Duchenne muscular dystrophy.ion channels | structure | cytoskeleton D uchenne muscular dystrophy affects 1:3,500 males, and in addition to skeletal muscle damage and atrophy, boys also develop a dilated cardiomyopathy due to the absence of expression of dystrophin. This pathology involves myocyte remodelling, disorganization of cytoskeletal proteins, and contractile dysfunction (1, 2). Early metabolic and signaling alterations have been reported in 10-to 12-wk-old murine model of Duchenne muscular dystrophy (mdx) hearts before the development of overt contractile dysfunction (2). However, the mechanisms by which absence of dystrophin leads to mitochondrial dysfunction and compromised cardiac function in mdx hearts are not fully clarified yet.Cytoskeletal proteins stabilize cell structure. In mature muscle, intermediate filaments form a 3D scaffold that extend from the Z disks to the plasma membrane and traverse cellular organelles such as t-tubules, sarcoplasmic reticulum, and mitochondria (3). Intermediate filaments and microtubules interact directly with mitochondria by binding to outer mitochondrial membrane proteins. In addition to a physical association, cytoskeletal proteins also regulate the function of proteins in the plasma membrane and within the cell (4). The L-type Ca 2+ channel (I Ca-L ) or dihydropyridine receptor (DHPR) is anchored to F-actin networks by subsarcolemmal sta...

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Section: Discussionmentioning

confidence: 80%

Impaired functional communication between the L-type calcium channel and mitochondria contributes to metabolic inhibition in the mdx heart

Viola

Adams

Davies

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…In addition, a stretch-induced increase in ROS production was completely abolished in the NOX2 knockout mice. The increased intracellular Ca 2+ response to mechanical challenge and hypersensitivity of EC coupling were normalized by both ROS scavengers and NOX inhibitors blockers (Jung et al 2007;Ullrich et al 2009;Prosser et al 2011). Taken together, and based on fact that ROS production occurs in the sarcolemmal and ttubule membranes in close proximity to NOX2, thus sensitising nearby RyRs in the SR, this may suggest that oxidation of RyRs is an early post-translational modification event in dystrophy.…”

Section: Contribution Of Oxidative Stress To Pathology In Muscular Dymentioning

confidence: 83%

“…The diaphragm muscle in the mdx mouse is highly susceptible to oxidative stress and shows a disease progression similar to human DMD (Disatnik et al 1998;Tkatchenko et al 2000;Hartel et al 2001). The damage observed in dystrophic cardiomyopathy is mainly caused by abnormalities of Ca 2+ signalling, particularly in the early stages of disease (Jung et al 2007;Prosser et al 2011). Antioxidant interventions with N-acetylcysteine in mdx mice consistently reduced ROS levels, normalized intracellular Ca 2+ levels, improved myofilament function and reduced cardiac inflammation and fibrosis (Williams and Allen 2007).…”

Section: Contribution Of Oxidative Stress To Pathology In Muscular Dymentioning

confidence: 97%

A change of heart: oxidative stress in governing muscle function?

Breitkreuz

Hamdani

2015

Biophys Rev

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Redox/cysteine modification of proteins that regulate calcium cycling can affect contraction in striated muscles. Understanding the nature of these modifications would present the possibility of enhancing cardiac function through reversible cysteine modification of proteins, with potential therapeutic value in heart failure with diastolic dysfunction. Both heart failure and muscular dystrophy are characterized by abnormal redox balance and nitrosative stress. Recent evidence supports the synergistic role of oxidative stress and inflammation in the progression of heart failure with preserved ejection fraction, in concert with endothelial dysfunction and impaired nitric oxide-cyclic guanosine monophosphate-protein kinase G signalling via modification of the giant protein titin. Although antioxidant therapeutics in heart failure with diastolic dysfunction have no marked beneficial effects on the outcome of patients, it, however, remains critical to the understanding of the complex interactions of oxidative/nitrosative stress with pro-inflammatory mechanisms, metabolic dysfunction, and the redox modification of proteins characteristic of heart failure. These may highlight novel approaches to therapeutic strategies for heart failure with diastolic dysfunction. In this review, we provide an overview of oxidative stress and its effects on pathophysiological pathways. We describe the molecular mechanisms driving oxidative modification of proteins and subsequent effects on contractile function, and, finally, we discuss potential therapeutic opportunities for heart failure with diastolic dysfunction.

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“…Moreover, it was recently reported that CaMKII can be activated in a Ca 2+ -independent way by reactive oxygen species (36). Interesting in this context is that Jung et al (23) provided evidence for increased levels of reactive oxygen species production in hearts of mdx mice.…”

Section: Discussionmentioning

confidence: 99%

Genetic inhibition of PKA phosphorylation of RyR2 prevents dystrophic cardiomyopathy

Sarma

Li²,

Oort³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Aberrant intracellular Ca 2+ regulation is believed to contribute to the development of cardiomyopathy in Duchenne muscular dystrophy. Here, we tested whether inhibition of protein kinase A (PKA) phosphorylation of ryanodine receptor type 2 (RyR2) prevents dystrophic cardiomyopathy by reducing SR Ca 2+ leak in the mdx mouse model of Duchenne muscular dystrophy. mdx mice were crossed with RyR2-S2808A mice, in which PKA phosphorylation site S2808 on RyR2 is inactivated by alanine substitution. Compared with mdx mice that developed age-dependent heart failure, mdx-S2808A mice exhibited improved fractional shortening and reduced cardiac dilation. Whereas application of isoproterenol severely depressed cardiac contractility and caused 95% mortality in mdx mice, contractility was preserved with only 19% mortality in mdx-S2808A mice. SR Ca 2+ leak was greater in ventricular myocytes from mdx than mdx-S2808A mice. Myocytes from mdx mice had a higher incidence of isoproterenol-induced diastolic Ca 2+ release events than myocytes from mdx-S2808A mice. Thus, inhibition of PKA phosphorylation of RyR2 reduced SR Ca 2+ leak and attenuated cardiomyopathy in mdx mice, suggesting that enhanced PKA phosphorylation of RyR2 at S2808 contributes to abnormal Ca 2+ homeostasis associated with dystrophic cardiomyopathy.calcium | cardiomyopathy | dystrophin | ryanodine receptor | sarcoplasmic reticulum

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Dystrophic cardiomyopathy: amplification of cellular damage by Ca2+ signalling and reactive oxygen species-generating pathways

Cited by 124 publications

References 35 publications

Impaired functional communication between the L-type calcium channel and mitochondria contributes to metabolic inhibition in the mdx heart

Impaired functional communication between the L-type calcium channel and mitochondria contributes to metabolic inhibition in the mdx heart

A change of heart: oxidative stress in governing muscle function?

Genetic inhibition of PKA phosphorylation of RyR2 prevents dystrophic cardiomyopathy

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