Revisiting the pathogenic role of insulin resistance in Duchenne muscular dystrophy cardiomyopathy subphenotypes

AbdelMassih, Antoine; Esmail, Reem; Zekri, Hanan; Kharabish, Ahmed; ElKhashab, Khaled; Menshawey, Rahma; Ismail, Habiba-Allah; Afdal, Peter; Farid, Erini; Affifi, Omneya

doi:10.1097/xce.0000000000000203

Cited by 3 publications

(4 citation statements)

References 25 publications

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“…Duchenne muscular dystrophy is often associated with metabolic complications such as IR, metabolic syndrome, and diabetes in boys/men with DMD ( 14 , 15 , 56 , 57 ) making nutritional management a critical component in the care of those with DMD ( 18 , 20 , 23 ). However, despite this frequency, the extent to which diet-induced IR (DI-IR) may promote disease progression and severity is unknown.…”

Section: Discussionmentioning

confidence: 99%

A fat- and sucrose-enriched diet causes metabolic alterations in mdx mice

Krishna,

Echevarria,

Reed

et al. 2023

American Journal of Physiology-Regulatory, Integrative and Comp

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Duchenne muscular dystrophy (DMD), a progressive muscle disease caused by the absence of functional dystrophin protein, is associated with multiple cellular, physiological, and metabolic dysfunctions. As an added complication to the primary insult, obesity/insulin resistance (O/IR) is frequently reported in DMD patients; however, how IR impacts disease severity is unknown. We hypothesized a high-fat, high sucrose diet (HFHSD) would induce O/IR, exacerbate disease severity, and cause metabolic alterations in dystrophic mice. To test this hypothesis, we treated 7-wk old mdx (disease model) and C57 mice with a control diet (CD) or a HFHSD for 15 weeks. The HFHSD induced insulin resistance, glucose intolerance and hyperglycemia in C57 and mdx mice. Of note, mdx mice on CD were also insulin resistant. Additionally, visceral adipose tissue weights were increased with HFHSD in C57 and mdx mice though differed by genotype. Serum creatine kinase activity and histopathological analyses using Masson's trichrome staining in diaphragm indicated muscle damage was driven by dystrophin deficiency but was not augmented by diet. In addition, markers of inflammatory signaling, mitochondrial abundance, and autophagy were impacted by disease but not diet. Despite this, in addition to disease signatures in CD-fed mice, metabolomic and lipidomic analyses demonstrated a HFHSD caused some common changes in C57 and mdx mice and some unique signatures of O/IR within the context of dystrophin deficiency. In total, these data revealed that in mdx mice, 15 weeks of a HFHSD did not overtly exacerbate muscle injury but further impaired the metabolic status of dystrophic muscle.

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Section: Discussionmentioning

confidence: 99%

A fat- and sucrose-enriched diet causes metabolic alterations in mdx mice

Krishna,

Echevarria,

Reed

et al. 2023

American Journal of Physiology-Regulatory, Integrative and Comp

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“…2). In addition, there may be a relationship between O/IR and disease-related cardiac phenotypes, raising the possibility that treating metabolic alterations in the early stages of the disease could be cardioprotective (9).…”

Section: Obesity and Insulin Resistance Augment Disease Progressionmentioning

confidence: 99%

“…In addition to muscle injury, DMD can have multisystemic consequences (9). Metabolic alterations associated with DMD include, but are not limited to, glucose intolerance, insulin resistance, hyperinsulinemia, and hyperglycemia (10,11).…”

Section: Introductionmentioning

confidence: 99%

The Interaction of Duchenne Muscular Dystrophy and Insulin Resistance

Krishna,

Quindry,

Valentine

et al. 2023

Exercise and Sport Sciences Reviews

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Duchenne muscular dystrophy (DMD), caused by deficiency of functional dystrophin protein, is a fatal, progressive muscle disease that frequently includes metabolic dysregulation. Herein, we explore the physiologic consequences of dystrophin deficiency within the context of obesity and insulin resistance. We hypothesized that dystrophin deficiency increases the frequency of insulin resistance, and insulin resistance potentiates muscle pathology caused by dystrophin deficiency.

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“…Dantrolene improved phosphorodiamidate morpholino oligomer (PMO) activity by enhancing PMO‐mediated exon‐skipping frequency, whereas hexose promoted PMO uptake via replenishing energy in energy‐deficient dystrophic muscles. However, the safety profiles for dantrolene need to be established and insulin resistance can be an issue for clinical use of hexose in DMD patients (AbdelMassih et al , 2020).…”

Section: Introductionmentioning

confidence: 99%

Cardio‐respiratory and phenotypic rescue of dystrophin/utrophin‐deficient mice by combination therapy

et al. 2022

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Duchenne muscular dystrophy (DMD) is a systemic progressive muscular disease caused by frame‐disrupting mutations in the DMD gene. Although exon‐skipping antisense oligonucleotides (AOs) are clinically approved and can correct DMD, insufficient muscle delivery limits efficacy. If AO activity can be enhanced by safe dietary supplements, clinical trials for efficacy can be undertaken rapidly to benefit patients. We showed previously that intravenous glycine enhanced phosphorodiamidate morpholino oligomer (PMO) delivery to peripheral muscles in mdx mice. Here, we demonstrate that the combination of oral glycine and metformin with intravenous PMO enhances PMO activity, dystrophin restoration, extends lifespan, and improves body‐wide function and phenotypic rescue of dystrophin /utrophin double knock‐out (DKO) mice without any overt adverse effects. The DKO mice treated with the combination without altering the approved administration protocol of PMO show improved cardio‐respiratory and behavioral functions. Metformin and glycine individually are ineffective in DMD patients, but the combination of PMO with clinically‐approved oral glycine and metformin might improve the efficacy of the treatment also in DMD patients. Our data suggest that this combination therapy might be an attractive therapy for DMD and potentially other muscle diseases requiring systemic treatment with AOs.

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Revisiting the pathogenic role of insulin resistance in Duchenne muscular dystrophy cardiomyopathy subphenotypes

Cited by 3 publications

References 25 publications

A fat- and sucrose-enriched diet causes metabolic alterations in mdx mice

A fat- and sucrose-enriched diet causes metabolic alterations in mdx mice

The Interaction of Duchenne Muscular Dystrophy and Insulin Resistance

Cardio‐respiratory and phenotypic rescue of dystrophin/utrophin‐deficient mice by combination therapy

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