Early myopathy in Duchenne muscular dystrophy is associated with elevated mitochondrial H₂O₂ emission during impaired oxidative phosphorylation

Abstract

Background Muscle wasting and weakness in Duchenne muscular dystrophy (DMD) causes severe locomotor limitations and early death due in part to respiratory muscle failure. Given that current clinical practice focuses on treating secondary complications in this genetic disease, there is a clear need to identify additional contributions in the aetiology of this myopathy for knowledge‐guided therapy development. Here, we address the unresolved question of whether the complex impairments observed in DMD are linked to elevated mitochondrial H 2 O 2 emission in conjunction with impaired oxidative phosphorylation. This study performed a systematic evaluation of the nature and degree of mitochondrial‐derived H 2 O 2 emission and mitochondrial oxidative dysfunction in a mouse model of DMD by designing in vitro bioenergetic assessments that attempt to mimic in vivo conditions known to be critical for the regulation of mitochondrial bioenergetics. Methods Mitochondrial bioenergetics were compared with functional and histopathological indices of myopathy early in DMD (4 weeks) in D2.B10‐DMD mdx /2J mice (D2. mdx )—a model that demonstrates severe muscle weakness. Adenosine diphosphate's (ADP's) central effect of attenuating H 2 O 2 emission while stimulating respiration was compared under two models of mitochondrial‐cytoplasmic phosphate exchange (creatine independent and dependent) in muscles that stained positive for membrane damage (diaphragm, quadriceps, and white gastrocnemius). Results Pathway‐specific analyses revealed that Complex I‐supported maximal H 2 O 2 emission was elevated concurrent with a reduced ability of ADP to attenuate emission during respiration in all three muscles (mH 2 O 2 : +17 to +197% in D2. mdx vs. wild type). This was associated with an impaired ability of ADP to stimulate respiration at sub‐maximal and maximal kinetics (−17 to −72% in D2. mdx vs. wild type), as well as a loss of creatine‐dependent mitochondrial phosphate shuttling in diaphragm and quadriceps. These changes largely occurred independent of mitochondrial density or abundance of respiratory chain complexes, except for quadriceps. This muscle was also the only one exhibiting decreased calcium retention capacity, which indicates increased sensitivity to calcium‐induced permeability transition pore opening. Increased H 2 O 2 emission was accompanied by a compensatory increase in total glutathione, while oxidative stress markers were unchanged. Mitochondrial b...

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

“…This schematic has been partially adapted from Hughes et al . () using concepts from Meyer et al . (), Aliev et al .…”

“…The PCr is exported via VDAC into the cytosol while the ADP is directly recycled back via ANT into the mitochondrial matrix. This schematic has been partially adapted from Hughes et al (2019) using concepts from Meyer et al (1984), Aliev et al (2011 and Guzun et al (2012).…”

Caveolin‐3 deficiency associated with the dystrophy P104L mutation impairs skeletal muscle mitochondrial form and function

“…However, given that mitochondrial dysfunction has been linked to muscle atrophy during muscle inactivity, disturbances in mitochondrial biology may also be a feature contributing to the development and progression of muscle‐wasting conditions. In support of this proposition, there is growing evidence linking mitochondrial dysfunction to a number of muscular dystrophies, including Duchenne, spinal muscular atrophy, and the calpainopathy that induces limb girdle muscular dystrophy Type 2A (LGMD2A) . Whether it is also a trait of caveolinopathies such as LGMD1C has not yet been documented, but studies in cultured myoblasts and mice expressing the Cav3 P104L mutation have reported disordered glucose metabolism and altered expression of a number of mitochondrial proteins that regulate diverse aspects of mitochondrial structure and function .…”

Transplantation of Muscle Stem Cell Mitochondria Rejuvenates the Bioenergetic Function of Dystrophic Muscle

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