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

Lin, Caorui; Hou, Gang; Jia, Lulu; Zhao, Yuemin; Jiang, Song; Ran, Ning; Yokota, Toshifumi; Seow, Yiqi; Yin, HaiFang

doi:10.15252/embr.202153955

Cited by 3 publications

(3 citation statements)

References 55 publications

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“…Wild‐type (WT) mice were purchased from Beijing Vital River Laboratory Animal Technology Company. DP1 global knockout (DP1 KO), DP2 KO, DP2 flox/flox (DP2 fl/fl ) and MDX mice were maintained in our laboratory 16,17 . DP2 fl/fl mice were crossed with human skeletal actin Cre (HSA Cre ) mice 18 to generate DP2 fl/fl HSA Cre mice.…”

Section: Methodsmentioning

confidence: 99%

“…DP1 global knockout (DP1 KO), DP2 KO, DP2 flox/flox (DP2 fl/fl ) and MDX mice were maintained in our laboratory. 16 , 17 DP2 fl/fl mice were crossed with human skeletal actin Cre (HSA Cre ) mice 18 to generate DP2 fl/fl HSA Cre mice. Mice were maintained in an environment with a controlled temperature (22 ± 1°C) and relative humidity (50 ± 5%) on a 12:12‐h light/dark cycle, with free access to a normal chow diet (ND) and water.…”

Section: Methodsmentioning

confidence: 99%

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Targeting the DP2 receptor alleviates muscle atrophy and diet‐induced obesity in mice through oxidative myofiber transition

Ning

Ren

Zhao

et al. 2022

J cachexia sarcopenia muscle

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Background Mammalian skeletal muscles consist of two main fibre types: slow‐twitch (type I, oxidative) and fast‐twitch (type IIa, fast oxidative; type IIb/IIx, fast glycolytic). Muscle fibre composition switch is closely associated with chronic diseases such as muscle atrophy, obesity, type II diabetes and athletic performance. Prostaglandin D2 (PGD2) is a bioactive lipid derived from arachidonic acid that aggravates muscle damage and wasting during muscle atrophy. This study aimed to investigate the precise mechanisms underlying PGD2‐mediated muscle homeostasis and myogenesis. Methods Skeletal muscle‐specific PGD2 receptor DP2‐deficient mice (DP2fl/flHSACre) and their littermate controls (DP2fl/fl) were subjected to exhaustive exercise and fed a high‐fat diet (HFD). X‐linked muscular dystrophy (MDX) mice and HFD‐challenged mice were treated with the selective DP2 inhibitor CAY10471. Exercise tolerance, body weight, glycometabolism and skeletal muscle fibre composition were measured to determine the role of the skeletal muscle PGD2/DP2 signalling axis in obesity and muscle disorders. Multiple genetic and pharmacological approaches were also used to investigate the intracellular signalling cascades underlying the PGD2/DP2‐mediated skeletal muscle fibre transition. Results PGD2 generation and DP2 expression were significantly upregulated in the hindlimb muscles of HFD‐fed mice (P < 0.05 or P < 0.01 vs. normal chow diet). Compared with DP2fl/fl mice, DP2fl/flHSACre mice exhibited remarkable glycolytic‐to‐oxidative fibre‐type transition in hindlimb muscles and were fatigue resistant during endurance exercise (154.9 ± 6.0 vs. 124.2 ± 8.1 min, P < 0.05). DP2fl/flHSACre mice fed an HFD showed less weight gain (P < 0.05) and hepatic lipid accumulation (P < 0.01), reduced insulin resistance and enhanced energy expenditure (P < 0.05) compared with DP2fl/fl mice. Mechanistically, DP2 deletion promoted the nuclear translocation of nuclear factor of activated T cells 1 (NFATc1) by suppressing RhoA/Rho‐associated kinase 2 (ROCK2) signalling, which led to enhanced oxidative fibre‐specific gene transcription in muscle cells. Treatment with CAY10471 enhanced NFATc1 activity in the skeletal muscles and ameliorated HFD‐induced obesity (P < 0.05 vs. saline) and insulin resistance in mice. CAY10471 also enhanced exercise tolerance in MDX mice (100.8 ± 8.0 vs. 68.9 ± 11.1 min, P < 0.05 vs. saline) by increasing the oxidative fibre‐type ratio in the muscles (45.1 ± 2.3% vs. 32.3 ± 2.6%, P < 0.05 vs. saline). Conclusions DP2 activation suppresses oxidative fibre transition via RhoA/ROCK2/NFATc1 signalling. The inhibition of DP2 may be a potential therapeutic approach against obesity and muscle disorders.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Targeting the DP2 receptor alleviates muscle atrophy and diet‐induced obesity in mice through oxidative myofiber transition

Ning

Ren

Zhao

et al. 2022

J cachexia sarcopenia muscle

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“…Based on previous studies that demonstrated an improvement of phosphorodiamidate morpholino oligomer (PMO) delivery to peripheral muscle in mdx mice by intravenous administration of glycine, the group conducted by Lin analyzed the effect of oral glycine and metformin alongside PMO in dystrophin/utrophin double knock-out (DKO) mice [55]. Thus, without any toxicity that could be detected and with a life span extension, the scientists demonstrated improvements in the cardio-respiratory and skeletal systems and a phenotypic rescue in DKO mice [55].…”

Section: Metformin: a Pleiotropic Drugmentioning

confidence: 99%

The Potential Benefits of Drug-Repositioning in Muscular Dystrophies

Lambrescu¹,

Manole²,

Ceafalan³

et al. 2023

Potential Therapeutic Strategies for Muscular Dystrophy

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Muscular dystrophies (MDs) are a complex group of rare neuromuscular disorders caused by genetic mutations that progressively weaken the muscles, resulting in an increasing level of disability. The underlying cause of these conditions consists of mutations in the genes in charge of a person’s muscle composition and functionality. MD has no cure, but medications and therapy can help control symptoms and slow the disease’s progression. Effective treatments have yet to be developed, despite the identification of the genetic origins and a thorough knowledge of the pathophysiological alterations that these illnesses induce. In this scenario, there is an urgent need for novel therapeutic options for these severe illnesses, and drug repositioning might be one feasible answer. In other words, drug repositioning/repurposing is an accelerated method of developing novel pharmaceuticals since the new indication is based on previously accessible safety, pharmacokinetic, and manufacturing data. This is particularly crucial for individuals with life-threatening illnesses such as MDs, who cannot wait for a conventional medication development cycle. This chapter aims to review the challenges and opportunities of drug-repositioning in a variety of MDs to establish novel treatment approaches for these incurable diseases.

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

Cited by 3 publications

References 55 publications

Targeting the DP2 receptor alleviates muscle atrophy and diet‐induced obesity in mice through oxidative myofiber transition

Targeting the DP2 receptor alleviates muscle atrophy and diet‐induced obesity in mice through oxidative myofiber transition

The Potential Benefits of Drug-Repositioning in Muscular Dystrophies

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

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