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

Abstract

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.

Metabolic Alterations in Cardiomyocytes of Patients with Duchenne and Becker Muscular Dystrophies

“…Very recently, it has been demonstrated that mitochondrial impairment anticipates the onset of cardiomyopathy in a mouse model of DMD [42]. In particular, elevated mitochondrial H 2 O 2 emission and impaired oxidative phosphorylation have been detected in the left ventricle muscle of these mice at an early age, when signs of cardiac dysfunction are absent, suggesting that mitochondrial dysfunction plays a role in the etiology of the heart disease occurring at an older age [42].…”

“…Oxidative stress that is present in mitochondria from dystrophic hearts, increased PTP opening, and activation of caspase 9/3 reported in young mdx hearts before the onset of cardiac impairment are all suggestive of mitochondria-derived apoptosis [41] (Figure 3). A very recent study demonstrates that, during altered oxidative phosphorylation, complex I-sustained emission of mitochondrial H 2 O 2 increases in the left ventricle of dystrophin-deficient young mice, before any evidence of cardiac dysfunction [42]. Therefore, the identification of early mitochondria-specific impairments may lead to the development of mitochondria-targeted therapies able to recover respiratory chain activity and bioenergetic control, with the aim to delay the onset of cardiomyopathy and the consequent progression to heart failure in DMD.…”

Satellite cell-derived extracellular vesicles reverse peroxide-induced mitochondrial dysfunction in myotubes

“…Mitochondrial dysfunction plays a central role in numerous muscular disorders and pathologies, including DMD [38,39]. For example, work by Hughes et al (2019) demonstrated that mitochondrial dysfunction, attributed to impaired oxidative phosphorylation and elevated oxidant production, contributes to early stage pathology in the D2.mdx mouse model [40]. Additionally, in the mdx mouse model, mitochondrial dysfunction is one of the earliest cellular consequences of DMD and is associated with the impaired ability of dystrophic muscle cells to respond to sarcolemmal damage [39].…”

“…Therefore, the purpose of this investigation was to characterize SC-EVs and examine potential therapeutic benefits in vitro. Importantly, mitochondrial damage has been causatively linked to impaired SC function [18,19] and impaired mitochondrial function is known to play a role in muscle atrophy, and/or weakness occurring in muscular dystrophy [20][21][22], cancer cachexia [23], disuse atrophy [24,25], mechanical ventilation-induced diaphragm weakness [26][27][28][29][30], sarcopenia [31,32], and chronic kidney disease [33]. With the established links between SC function and mitochondrial function [34], we also investigated the extent to which SC-EVs could attenuate mitochondrial dysfunction.…”

Mechanics and energetics in cardiac arrhythmias and heart failure

“…Hughes et al . (2020) investigated the remodelling of mitochondria energetics and cardiac dysfunction in Duchenne muscular dystrophy (DMD). Using the D2.B10‐DMD mdx /2J mice – an animal model that demonstrates skeletal muscle atrophy and weakness due to limited regenerative capacities and cardiomyopathy more akin to people with DMD – they discovered impairments in ADP‐stimulated respiration and ADP attenuation of H 2 O 2 emission.…”