Mitochondrial Dysfunction Is an Early Consequence of Partial or Complete Dystrophin Loss in mdx Mice

Abstract

Duchenne muscular dystrophy (DMD) is characterized by rapid wasting of skeletal muscle. Mitochondrial dysfunction is a well-known pathological feature of DMD. However, whether mitochondrial dysfunction occurs before muscle fiber damage in DMD pathology is not well known. Furthermore, the impact upon heterozygous female mdx carriers (mdx/+), who display dystrophin mosaicism, has received little attention. We hypothesized that dystrophin deletion leads to mitochondrial dysfunction, and that this may occur before myofiber necrosis. As a secondary complication to mitochondrial dysfunction, we also hypothesized metabolic abnormalities prior to the onset of muscle damage. In this study, we detected aberrant mitochondrial morphology, reduced cristae number, and large mitochondrial vacuoles from both male and female mdx mice prior to the onset of muscle damage. Furthermore, we systematically characterized mitochondria during disease progression starting before the onset of muscle damage, noting additional changes in mitochondrial DNA copy number and regulators of mitochondrial size. We further detected mild metabolic and mitochondrial impairments in female mdx carrier mice that were exacerbated with high-fat diet feeding. Lastly, inhibition of the strong autophagic program observed in adolescent mdx male mice via administration of the autophagy inhibitor leupeptin did not improve skeletal muscle pathology. These results are in line with previous data and suggest that before the onset of myofiber necrosis, mitochondrial and metabolic abnormalities are present within the mdx mouse.

Metformin Reverses the Enhanced Myocardial SR/ER–Mitochondria Interaction and Impaired Complex I-Driven Respiration in Dystrophin-Deficient Mice

“…In parallel, DMD is associated with a progressive deterioration of the mitochondrial ultrastructure and function (Kyrychenko et al, 2015 ). Mitochondrial defects were mainly characterized in skeletal muscle where a significant uncoupling of the oxidative phosphorylation, defects in complex I, and a reduction of ATP synthesis were observed (Sperl et al, 1997 ; Kuznetsov et al, 1998 ; Percival et al, 2013 ; Rybalka et al, 2014 ; Moore et al, 2020 ). In heart muscle, a metabolic shift from fatty acid oxidation to carbohydrate oxidation has also been observed prior to the onset of DCM and heart failure (Khairallah et al, 2007 , 2008 ; Burelle et al, 2010 ).…”

Mitochondrial hydrogen sulfide supplementation improves health in the C. elegans Duchenne muscular dystrophy model

“…Destabilization of this complex from the reduction of dystrophin results in progressive muscle-fiber damage and membrane leakage ( 2 ). In addition, reduction of dystrophin causes increased sarcoplasmic calcium levels, which may cause a cascade of detrimental effects, including mitochondrial damage ( 3 – 7 ). DMD is a disorder that affects over 1 in 3,500 live male births.…”

Targeting Nrf2 for the treatment of Duchenne Muscular Dystrophy

“…p62 expression is regulated in a Nrf2-dependant manner, forming a positive feedback loop to amplify its Nrf2-activator function [ 93 ]. In mdx mice, mitophagy is impaired due to defective PINK1/Parkin signalling [ 153 , 155 ]. Furthermore, Murata et al demonstrated that stress-damaged mitochondria induce Nrf2-dependant transcription of the PINK1 gene [ 156 ], indicating that PINK1 expression is positively regulated by Nrf2.…”