MOTS‐c promotes phosphorodiamidate morpholino oligomer uptake and efficacy in dystrophic mice

Ran, Ning; Lin, Caorui; Leng, Ling; Hou, Gang; Geng, Mengyuan; Wu, Yingjie; Bittner, Scott; Moulton, Hong M.; Yin, HaiFang

doi:10.15252/emmm.202012993

Cited by 9 publications

(10 citation statements)

References 47 publications

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“…A recent study also indicated that administration of MOTS-c elicited therapeutic levels without any detectable toxicity. 18 The evidence indicated that MOTS-c might be a more effective and safer peptide than drugs or microRNAs in the clinical treatment of CVD.…”

Section: Discussionmentioning

confidence: 99%

The Mitochondrial-Derived Peptide MOTS-c Attenuates Oxidative Stress Injury and the Inflammatory Response of H9c2 Cells Through the Nrf2/ARE and NF-κB Pathways

Shen

Wang

Feng

et al. 2021

Cardiovasc Eng Tech

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Aim-Oxidative stress and the inflammatory response contribute to the progression of cardiovascular disease. The present study aimed to investigate whether the mitochondrial-derived peptide MOTS-c could alleviate H 2 O 2 -induced oxidative stress and inflammatory status in H9c2 cells through activation of nuclear factor erythroid 2-related Factor 2 (Nrf2)/antioxidative response element (ARE) and inhibition of the NF-jB pathway. Methods-Rat H9c2 cardiomyocytes were obtained, and 10, 20 or 50 lM MOTS-c was pretreated for 24 h before treatment with H 2 O 2. Then, the cell was treated with 100 lM H 2 O 2 for 1 h to induce oxidative stress. An inhibition model of sh-Nrf2 was constructed via a lentivirus expression system, and an activation model of NF-jB was achieved using phorbol 12-myristate-13-acetate (PMA). Cell viability was determined using a Cell Counting kit-8 assay. Relative measurement of relative protein and mRNA expression used western blotting and qRT-PCR, respectively. Intracellular reactive oxygen species (ROS) levels were detected using dichlorodihydrofluorescein diacetate, and malondialdehyde (MDA) and superoxide dismutase (SOD) levels were determined via commercial kits. The protein expression and distribution in the cells were visualized by immunofluorescence analysis. Enzyme-linked immunosorbent assay was used to detect the levels of inflammatory cytokines, including TNF-a, IL-6 and IL-1b. Results-We found that H 2 O 2 treatment significantly decreased cell viability and the level of SOD, increased the levels of ROS and MDA, and upregulated the expression of inflammatory cytokines, including TNF-a, IL-6 and IL-1b, in H9c2 cells. The expression levels of Nrf2, HO-1 and NQO-1 were significantly downregulated in the H 2 O 2 , while the phosphorylation of NF-jBp65 was promoted by H 2 O 2 . However, pretreatment with MOTS-c significantly reversed H 2 O 2 -induced damage in H9c2 cells. Moreover, both inhibition of the Nrf2/ARE pathway and activation of the NF-jB pathway significantly decreased the effects of MOTS-c, suggesting that MOTS-c might play a role in alleviating oxidative damage via the Nrf2/ARE and NF-jB pathways. Conclusions-Our investigation indicated that MOTS-c could protect against H 2 O 2 -induced inflammation and oxidative stress in H9c2 cells by inhibiting NF-jB and activating the Nrf2/ARE pathways.

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Section: Discussionmentioning

confidence: 99%

The Mitochondrial-Derived Peptide MOTS-c Attenuates Oxidative Stress Injury and the Inflammatory Response of H9c2 Cells Through the Nrf2/ARE and NF-κB Pathways

Shen

Wang

Feng

et al. 2021

Cardiovasc Eng Tech

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Section: Mots-c Inhibits Pathological Metabolic Processesmentioning

confidence: 99%

“…Previous research has shown that MOTS-c was naturally muscle-targeting, which could speed up skeletal muscle metabolism while generating energy [ 31 ]. MOTS-c increases the level of glycolysis and ATP in dystrophic muscle cells, enhancing the absorption and activity of phosphorodiamidate morpholino oligomer [ 31 ]. Additionally, it was found that by giving a long-term combined administration of MOTS-c and phosphorodiamidate morpholino oligomer to Duchenne muscular dystrophy (DMD)-affected mice, their muscular functions significantly improved [ 31 ].…”

Section: Mots-c Inhibits Pathological Metabolic Processesmentioning

confidence: 99%

“…MOTS-c increases the level of glycolysis and ATP in dystrophic muscle cells, enhancing the absorption and activity of phosphorodiamidate morpholino oligomer [ 31 ]. Additionally, it was found that by giving a long-term combined administration of MOTS-c and phosphorodiamidate morpholino oligomer to Duchenne muscular dystrophy (DMD)-affected mice, their muscular functions significantly improved [ 31 ]. Therefore, MOTS-c can be utilized as an adjuvant to enhance the therapeutic effect of oligonucleotide-mediated exon-skipping therapy for insulin-resistance-induced skeletal muscle atrophy [ 31 , 32 ].…”

Section: Mots-c Inhibits Pathological Metabolic Processesmentioning

confidence: 99%

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MOTS-c Functionally Prevents Metabolic Disorders

Gao

Wei

et al. 2023

Metabolites

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Mitochondrial-derived peptides are a family of peptides encoded by short open reading frames in the mitochondrial genome, which have regulatory effects on mitochondrial functions, gene expression, and metabolic homeostasis of the body. As a new member of the mitochondrial-derived peptide family, mitochondrial open reading frame of the 12S rRNA-c (MOTS-c) is regarding a peptide hormone that could reduce insulin resistance, prevent obesity, improve muscle function, promote bone metabolism, enhance immune regulation, and postpone aging. MOTS-c plays these physiological functions mainly through activating the AICAR-AMPK signaling pathways by disrupting the folate-methionine cycle in cells. Recent studies have shown that the above hormonal effect can be achieved through MOTS-c regulating the expression of genes such as GLUT4, STAT3, and IL-10. However, there is a lack of articles summarizing the genes and pathways involved in the physiological activity of MOTS-c. This article aims to summarize and interpret the interesting and updated findings of MOTS-c-associated genes and pathways involved in pathological metabolic processes. Finally, it is expected to develop novel diagnostic markers and treatment approaches with MOTS-c to prevent and treat metabolic disorders in the future.

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“…Different approaches have been under intense scrutiny for enhancing the delivery of AOs to muscle including cell‐penetrating peptides (Moulton & Moulton, 2010), tissue‐targeting peptides (Gao et al , 2014), chimeric (Yin et al , 2010), and energy‐replenishing peptides (Ran et al , 2021), though the safety of these peptides remains to be determined. Synthetic or biological nanoparticles such as polymers or exosomes have also been utilized to enhance AO delivery to dystrophic muscles (Falzarano et al , 2014; Gao et al , 2018).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

Self Cite

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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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MOTS‐c promotes phosphorodiamidate morpholino oligomer uptake and efficacy in dystrophic mice

Cited by 9 publications

References 47 publications

The Mitochondrial-Derived Peptide MOTS-c Attenuates Oxidative Stress Injury and the Inflammatory Response of H9c2 Cells Through the Nrf2/ARE and NF-κB Pathways

The Mitochondrial-Derived Peptide MOTS-c Attenuates Oxidative Stress Injury and the Inflammatory Response of H9c2 Cells Through the Nrf2/ARE and NF-κB Pathways

MOTS-c Functionally Prevents Metabolic Disorders

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

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