Stress-induced opening of the permeability transition pore in the dystrophin-deficient heart is attenuated by acute treatment with sildenafil

Abstract

Susceptibility of cardiomyocytes to stress-induced damage has been implicated in the development of cardiomyopathy in Duchenne muscular dystrophy, a disease caused by the lack of the cytoskeletal protein dystrophin in which heart failure is frequent. However, the factors underlying the disease progression are unclear and treatments are limited. Here, we tested the hypothesis of a greater susceptibility to the opening of the mitochondrial permeability transition pore (PTP) in hearts from young dystrophic (mdx) mice (before the development of overt cardiomyopathy) when subjected to a stress protocol and determined whether the prevention of a PTP opening is involved in the cardioprotective effect of sildenafil, which we have previously reported in mdx mice. Using the 2-deoxy-[(3)H]glucose method to quantify the PTP opening in ex vivo perfused hearts, we demonstrate that when compared with those of controls, the hearts from young mdx mice subjected to ischemia-reperfusion (I/R) display an excessive PTP opening as well as enhanced activation of cell death signaling, mitochondrial oxidative stress, cardiomyocyte damage, and poorer recovery of contractile function. Functional analyses in permeabilized cardiac fibers from nonischemic hearts revealed that in vitro mitochondria from mdx hearts display normal respiratory function and reactive oxygen species handling, but enhanced Ca(2+) uptake velocity and premature opening of the PTP, which may predispose to I/R-induced injury. The administration of a single dose of sildenafil to mdx mice before I/R prevented excessive PTP opening and its downstream consequences and reduced tissue Ca(2+) levels. Furthermore, mitochondrial Ca(2+) uptake velocity was reduced following sildenafil treatment. In conclusion, beyond our documentation that an increased susceptibility to the opening of the mitochondrial PTP in the mdx heart occurs well before clinical signs of overt cardiomyopathy, our results demonstrate that sildenafil, which is already administered in other pediatric populations and is reported safe and well tolerated, provides efficient protection against this deleterious event, likely by reducing cellular Ca(2+) loading and mitochondrial Ca(2+) uptake.

Mitochondrial dysfunctions during progression of dystrophic cardiomyopathy

“…Various structural, biochemical and functional mitochondrial abnormalities have been reported for dystrophic skeletal and cardiac muscle [10,32,33]. Among them is a predisposition of mitochondria from mdx hearts to an increased propensity of mPTP opening during ischemia-reperfusion [14,22]. Our results show that during the progression of dystrophic cardiac myopathy there is an accumulation of dysfunctional mitochondria.…”

Human iPSC-Derived Neural Progenitors Are an Effective Drug Discovery Model for Neurological mtDNA Disorders

“…The positive effects of avanafil on calcium homeostasis may thus be due to its effects on cellular polarization, which are similar to those of acetazolamide, and/or to its triggering of a slight mitochondrial depolarization, which would directly influence mitochondrial calcium homeostasis ( Figure 7K). Yet another possibility is that PDE5 inhibitors affect the opening of the PTP (Ascah et al, 2011). Further studies will be needed to clarify the mode by which avanafil and PDE5 inhibitors act in the context of MT-ATP6-associated neural impairment.…”

Nicorandil, a Nitric Oxide Donor and ATP-Sensitive Potassium Channel Opener, Protects Against Dystrophin-Deficient Cardiomyopathy

“…For example, restoration of the NO-cGMP pathway 3,49,50 with phosphodiesterase-5 inhibitors, such as sildenafil, improved cardiac pathology in mdx mice. 49,50 However, these outcomes have not translated to clinical improvements in patients with Duchenne or Becker muscular dystrophy. 51,52 Explanations for this lack of clinical benefit of restoring the NO-cGMP pathway could be due to (1) an increase in oxidative stress in the heart or (2) beneficial NO actions independent of cGMP signaling that are not restored by phosphodiesterase-5 inhibitors.…”