Impaired substrate utilization in mitochondria from strain 129 dystrophic mice

Martens, Margaret E.; Jankulovska, L; Neymark, Michael A.; Lee, C.P.

doi:10.1016/0005-2728(80)90037-7

Cited by 9 publications

(5 citation statements)

References 26 publications

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“…NAD is a cofactor at multiple sites of the tricarboxylic acid (TCA) cycle and in glycolysis, and contributes to the generation of the mitochondrial membrane potential, which is the driving force for ATP production. 39 Because the total NAD pool was decreased in the dystrophic muscle, 40 we analyzed NAD and NADH levels in muscle. Consistent with the ATP data, an evident increase in levels of both NAD and NADH was found in muscle from PMO-GF-treated mdx mice compared with age-matched untreated mdx controls ( Figure 5 B).…”

Section: Resultsmentioning

confidence: 99%

Long-Term Morpholino Oligomers in Hexose Elicit Long-Lasting Therapeutic Improvements in mdx Mice

Hou

Lin

Ning

et al. 2018

Molecular Therapy - Nucleic Acids

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Approval of antisense oligonucleotide eteplirsen highlights the promise of exon-skipping therapeutics for Duchenne muscular dystrophy patients. However, the limited efficacy of eteplirsen underscores the importance to improve systemic delivery and efficacy. Recently, we demonstrated that a glucose and fructose (GF) delivery formulation effectively potentiates phosphorodiamidate morpholino oligomer (PMO). Considering the clinical potential of GF, it is important to determine the long-term compatibility and efficacy with PMO in mdx mice prior to clinical translation. Here, we report that yearlong administration of a clinically applicable PMO dose (50 mg/kg/week for 3 weeks followed by 50 mg/kg/month for 11 months) with GF elicited sustainably high levels of dystrophin expression in mdx mice, with up to 45% of the normal level of dystrophin restored in most peripheral muscles without any detectable toxicity. Importantly, PMO-GF resulted in phenotypical rescue and mitochondrial biogenesis with functional improvement. Carbohydrate metabolites measurements revealed improved metabolic and energetic conditions after PMO-GF treatment in mdx mice without metabolic anomaly. Collectively, our study shows PMO-GF’s ability to elicit long-lasting therapeutic effects with tolerable toxicity and represents a new treatment modality for Duchenne muscular dystrophy, and provides guidelines for antisense oligonucleotides with GF in clinical use.

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Section: Resultsmentioning

confidence: 99%

Long-Term Morpholino Oligomers in Hexose Elicit Long-Lasting Therapeutic Improvements in mdx Mice

Hou

Lin

Ning

et al. 2018

Molecular Therapy - Nucleic Acids

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“…We hypothesised that ASA could improve the metabolic capacity of dystrophic muscles by enhancing PNC function and thus purine nucleotide salvage, but particularly, by increasing fumarate production and anaplerosis of the mitochondrial TCA cycle 14,19 . Despite having previously demonstrated an impaired mitochondrial ATP production rate in isolated mdx mitochondrial bathed in optimal TCA substrate cocktails 17 , we and others have shown a partial attenuation of this mitochondrial dysfunction by stimulating CII with succinate [25][26][27][28][79][80][81] . Thus, we predicted in this study that promoting anaplerosis could, at the very least, augment SDH activity and the respiratory capacity of CII-mediated OXPHOS.…”

Section: Discussionmentioning

confidence: 83%

“…Recently, it has been demonstrated that ASA stimulates exocytosis of insulin from pancreatic β cells, and that inhibition of ASA's regulatory enzymes within the PNC impairs glucose-stimulated insulin secretion 24 . This suggests that ASA activates energy producing pathways, which could be beneficial to overcome the chronic metabolic impairment of dystrophin-deficient muscles 17,[25][26][27][28][29][30][31] .…”

mentioning

confidence: 99%

Adenylosuccinic acid therapy ameliorates murine Duchenne Muscular Dystrophy

Timpani

Goodman

Stathis

et al. 2020

Sci Rep

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Arising from the ablation of the cytoskeletal protein dystrophin, Duchenne Muscular Dystrophy (DMD)is a debilitating and fatal skeletal muscle wasting disease underpinned by metabolic insufficiency. The inability to facilitate adequate energy production may impede calcium (Ca 2+ ) buffering within, and the regenerative capacity of, dystrophic muscle. Therefore, increasing the metabogenic potential could represent an effective treatment avenue. The aim of our study was to determine the efficacy of adenylosuccinic acid (ASA), a purine nucleotide cycle metabolite, to stimulate metabolism and buffer skeletal muscle damage in the mdx mouse model of DMD. Dystrophin-positive control (C57BL/10) and dystrophin-deficient mdx mice were treated with ASA (3000 µg.mL −1 ) in drinking water. Following the 8-week treatment period, metabolism, mitochondrial density, viability and superoxide (O 2 − ) production, as well as skeletal muscle histopathology, were assessed. ASA treatment significantly improved the histopathological features of murine DMD by reducing damage area, the number of centronucleated fibres, lipid accumulation, connective tissue infiltration and Ca 2+ content of mdx tibialis anterior. These effects were independent of upregulated utrophin expression in the tibialis anterior. ASA treatment also increased mitochondrial viability in mdx flexor digitorum brevis fibres and concomitantly reduced o 2 − production, an effect that was also observed in cultured immortalised human DMD myoblasts. Our data indicates that ASA has a protective effect on mdx skeletal muscles.

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“…In fact, mitochondrial dysfunction has been shown to occur before the onset of myofiber necrosis, muscle wasting and myofibrillar defects [253]. Impaired substrate utilization and ATP synthesis have been reported in dystrophic mitochondria [254,255]. There occurs an uncoupling in the process of mitochondrial oxidative phosphorylation during the progression of muscular dystrophy [256,257].…”

Section: Mechanisms Of Subcellular Ca 2+ -Handling Abnormalities In Dystrophic Musclementioning

confidence: 99%

Role of molecular and metabolic defects in impaired performance of dystrophic skeletal muscles

Bhullar¹,

Nusier²,

Shah³

et al. 2021

J. Mol. Clin. Med.

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There occurs a progressive weakness and wastage of skeletal muscle in different types of muscular dystrophy. The loss of muscle fibers in dystrophic muscle with impaired function is associated with leakage of intracellular enzymes, maldistribution of electrolyte content and metabolic defects in myocytes. Marked increases in the sarcolemma (SL) Na+-K+ ATPase and Ca2+/Mg2+-ecto ATPase activities, as well as depressions in the sarcoplasmic reticulum (SR) Ca2+-uptake and Ca2+-pump ATPase activities were seen in dystrophic muscles of a hamster model of myopathy. In addition, impaired mitochondrial oxidative phosphorylation and decrease in the high energy stores as a consequence of mitochondrial Ca2+-overload were observed in these myopathic hamsters. In some forms of muscular dystrophy, it has been shown that deficiency of dystrophin produces marked alterations in the SL permeability and promotes the occurrence of intracellular Ca2+-overload for inducing metabolic defects, activation of proteases and contractile abnormalities in dystrophic muscle. Increases in SR Ca2+-release channels, SL Na+-Ca2+ exchanger and SL store-operated Ca2+-channels have been reported to induce Ca2+-handling abnormalities in a mouse model of muscular dystrophy. Furthermore, alterations in lipid metabolism and development of oxidative stress have been suggested as mechanisms for subcellular remodeling and cellular damage in dystrophic muscle. Although, several therapeutic interventions including gene therapy are available, these treatments neither fully prevent the course of development of muscular disorder nor fully improve the function of dystrophic muscle. Thus, extensive reasearch work with some novel inhibitors of oxidative stress, SL Ca2+-entry systems such as store-operated Ca2+-channels, Na+-Ca2+ exchanger and Ca2+/Mg2+-ecto ATPase (Ca2+-gating mechanism), as well as SR Ca2+-release and Ca2+-pump systems needs to be carried out in combination of gene therapy for improved beneficial effects in muscular dystrophy.

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Impaired substrate utilization in mitochondria from strain 129 dystrophic mice

Cited by 9 publications

References 26 publications

Long-Term Morpholino Oligomers in Hexose Elicit Long-Lasting Therapeutic Improvements in mdx Mice

Long-Term Morpholino Oligomers in Hexose Elicit Long-Lasting Therapeutic Improvements in mdx Mice

Adenylosuccinic acid therapy ameliorates murine Duchenne Muscular Dystrophy

Role of molecular and metabolic defects in impaired performance of dystrophic skeletal muscles

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