Mitochondrial content is preserved throughout disease progression in the <i>mdx</i> mouse model of Duchenne muscular dystrophy, regardless of taurine supplementation

Barker, Robert G.; Wyckelsma, Victoria L.; Xu, Hongyang

doi:10.1152/ajpcell.00046.2017

Cited by 19 publications

(15 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We further observed impaired complex IV enzymatic activity as previously described (Gaglianone et al, 2019). While not extensively tested, published research does suggest a mitochondrial phenotype occurring early in muscular dystrophy disease progression (Nghiem et al, 2017;Vila et al, 2017;Barker et al, 2018). These data suggest that a connection may exist between mitochondria, dystrophin, and muscle fiber damage, at least in a mouse model of muscular dystrophy.…”

Section: Discussionsupporting

confidence: 82%

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

et al. 2020

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 82%

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

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Furthermore, low/physiological to high concentrations of ADP were unable to attenuate mH 2 O 2 to the same extent as WT. The impaired control by ADP in skeletal muscle may not be related to changes in mitochondrial content given ETC markers were unchanged in diaphragm and WG similar to what has been reported recently in C57bl/10‐ mdx mouse soleus and extensor digitorum longus . Rather, this may be explained partially by limited ADP/ATP exchange due to decreased protein expression of VDAC 2 and ANT 1 in Quad and WG, or octameric mtCK, the regulator of high energy phosphate shuttling.…”

Section: Discussionsupporting

confidence: 76%

“…The impaired control by ADP in skeletal muscle may not be related to changes in mitochondrial content given ETC markers were unchanged in diaphragm and WG similar to what has been reported recently in C57bl/10-mdx mouse soleus and extensor digitorum longus. 58 Rather, this may be explained partially by limited ADP/ATP exchange due to decreased protein expression of VDAC 2 and ANT 1 in Quad and WG, or octameric mtCK, the regulator of high energy phosphate shuttling. There was no change in the content of these proteins in diaphragm, which suggests that posttranslational regulation of these proteins may have been altered.…”

Section: Concurrent Impairments In Complex I and Governance By Adenosmentioning

confidence: 99%

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

Hughes

Turnbull

Rebalka

et al. 2019

J cachexia sarcopenia muscle

106

126

View full text Add to dashboard Cite

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...

show abstract

“…We further observed impaired complex IV enzymatic activity. Nevertheless, published research does suggest a mitochondrial phenotype occurring early in muscular dystrophy disease progression (66,67). These data suggest that a connection may exist between mitochondria, dystrophin, and muscle fiber damage at least in a mouse model of muscular dystrophy.…”

Section: Discussionmentioning

confidence: 94%

Mitochondrial dysfunction is an early consequence of partial or complete dystrophin loss in mdx mice.

Moore

Lin

Strumwasser

et al. 2020

Preprint

View full text Add to dashboard Cite

Background:Muscular dystrophies are a diverse family of genetic and hereditary disorders manifested primarily by the progressive wasting of skeletal muscle. Duchenne muscular dystrophy (DMD), the most common muscular dystrophy, has no cure, with most treatments seeking to mitigate symptoms. Emerging gene or stem cell therapies hold promise, although widespread clinical adoption may not occur for quite some time. There remains a need for alternative strategies, including drug and lifestyle combination-based therapies, and to continue furthering understanding the physiological effects of dystrophin gene mutations. Mitochondrial dysfunction is well known as a pathological feature of DMD. However, whether mitochondrial dysfunction is a cause or the consequence of DMD is not well known. We hypothesized that dystrophin deletion would lead to mitochondrial and metabolic abnormalities prior to the onset of observable muscle damage.Methods:Utilizing the commonly employed muscular dystrophy mouse model, C57BL/10ScSn-Dmdmdx/J (mdx), we sought to determine how the loss of dystrophin effects mitochondria and metabolism in both male and female mdx mice. We also treated male mdx mice with an autophagy inhibitor, leupeptin, to investigate its potentially impact on mdx pathology.Results:We detected, via electron microscopy, aberrant mitochondrial morphology, reduced cristae numbers per area of mitochondria, and large mitochondrial vacuoles from both two-week-old male and 24-week-old female mdx carrier mice, prior to the onset of visible muscle fiber damage. We systematically characterized mitochondria during disease progression starting before the onset of gross muscle fiber damage noting changes in mitochondrial DNA copy number and regulators of mitochondrial size. We further detected mild metabolic and mitochondrial impairments in female mdx carrier mice (heterozygous mdx/+) that was exacerbated with high-fat diet feeding. Lastly, we found autophagy inhibition did not improve pathology in mdx male mice.Conclusions:Our results suggest that prior to the onset of visible muscle damage, mitochondrial and metabolic abnormalities are present within the mdx mouse.

show abstract

Mitochondrial content is preserved throughout disease progression in the mdx mouse model of Duchenne muscular dystrophy, regardless of taurine supplementation

Cited by 19 publications

References 38 publications

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

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

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

Mitochondrial dysfunction is an early consequence of partial or complete dystrophin loss in mdx mice.

Contact Info

Product

Resources

About

Mitochondrial content is preserved throughout disease progression in the mdx mouse model of Duchenne muscular dystrophy, regardless of taurine supplementation

Cited by 19 publications

References 38 publications

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

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

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

Mitochondrial dysfunction is an early consequence of partial or complete&nbsp;dystrophin loss in&nbsp;mdx&nbsp;mice.

Contact Info

Product

Resources

About

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

Mitochondrial dysfunction is an early consequence of partial or complete dystrophin loss in mdx mice.