Ghrelin improves muscle function in dystrophin-deficient mdx mice by inhibiting NLRP3 inflammasome activation

Chang, Leilei; Niu, Fengnan; Chen, Jian; Cao, Xiang; Liu, Zhuo; Bao, Xinyu; Xu, Yun

doi:10.1016/j.lfs.2019.116654

Cited by 23 publications

(26 citation statements)

References 31 publications

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“…In order to evaluate whether the administration of ONX-0914 is beneficial during the acute phase of intensive myofiber degeneration and regeneration, the initial step in the current study required the identification of the motor function and morphological characteristics of muscle in MDX mice at seven weeks of age. The findings corroborate the evidence that in 7-week old MDX mice, there are clear motor deficits and the muscles are present with bouts of myofiber degeneration/regeneration [ 7 , 10 , 12 , 47 , 48 ]. The reported 59% centrally placed nuclei within the myofibers are in line with lifespan studies demonstrating an enhanced regenerative state at this age [ 49 , 50 ].…”

Section: Discussionsupporting

confidence: 87%

Short-Term ONX-0914 Administration: Performance and Muscle Phenotype in Mdx Mice

Kwak

Wei

Thompson

et al. 2020

IJERPH

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Duchenne muscular dystrophy (DMD) is a severe muscle-wasting disease. Although the lack of dystrophin protein is the primary defect responsible for the development of DMD, secondary disease complications such as persistent inflammation contribute greatly to the pathogenesis and the time-dependent progression of muscle destruction. The immunoproteasome is a potential therapeutic target for conditions or diseases mechanistically linked to inflammation. In this study, we explored the possible effects of ONX-0914 administration, an inhibitor specific for the immunoproteasome subunit LMP7 (ß5i), on motor performance, muscular pathology and protein degradation in 7-week old MDX mice, an age when the dystrophic muscles show extensive degeneration and regeneration. ONX-0914 (10 mg/kg) was injected subcutaneously on Day 2, 4, and 6. The mice were evaluated for physical performance (walking speed and strength) on Day 1 and 8. We show that this short-term treatment of ONX-0914 in MDX mice did not alter strength nor walking speed. The physical performance findings were consistent with no change in muscle inflammatory infiltration, percentage of central nuclei and proteasome content. Taken together, muscle structure and function in the young adult MDX mouse model are not altered with ONX-0914 treatment, indicating the administration of ONX-0914 during this critical time period does not exhibit any detrimental effects and may be an effective treatment of secondary complications of muscular dystrophy after further investigations.

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Section: Discussionsupporting

confidence: 87%

Short-Term ONX-0914 Administration: Performance and Muscle Phenotype in Mdx Mice

Kwak

Wei

Thompson

et al. 2020

IJERPH

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“…PBS and ghrelin were injected subcutaneously. The dose of ghrelin used in our experiments was consistent with that used in similar studies (Chang et al, 2019; Ling et al, 2019). According to our previous work, the peak EAE onset, on about day 14, was a suitable time to collect blood samples and acquire brain and spinal cord (lumbar enlargement) tissues (Yang et al, 2016).…”

Section: Methodssupporting

confidence: 86%

Ghrelin Attenuates Neuroinflammation and Demyelination in Experimental Autoimmune Encephalomyelitis Involving NLRP3 Inflammasome Signaling Pathway and Pyroptosis

Liu¹,

Li²,

He³

et al. 2019

Front. Pharmacol.

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Multiple sclerosis (MS) is a chronic autoimmune and degenerative disease of the central nervous system, and conventional treatments have limited efficacy or side effects. Ghrelin, a 28-amino acid octanoylated peptide, has been reported to have neuroprotective effects, including anti-oxidation, anti-inflammation, and anti-apoptosis. Pyroptosis, also called inflammatory cell death, is triggered by overly active inflammasomes and accompanied by the production of numerous cytokines. As immune dysfunction is primarily involved in the pathogenesis of MS, this study aimed to explore the therapeutic effects and precise functional mechanisms of ghrelin against the nod-like receptor protein 3 (NLRP3) inflammasome and pyroptosis in experimental autoimmune encephalomyelitis (EAE). Sprague Dawley rats were immunized with guinea pig spinal cord homogenates and pertussis toxin to develop an EAE model. All rats were randomly divided into four groups: normal control group, EAE group, EAE + ghrelin group, and ghrelin control group. EAE rats showed abnormal behavioral scores and body weight changes. Histologic analysis displayed severe inflammatory infiltration and demyelination in the brain and spinal cord of EAE rats. Ghrelin treatments potently restored these abnormal changes. In addition, the ghrelin-treated EAE group showed significantly downregulated expression of inflammatory cytokines. The expression of proteins involved in the NLRP3 signaling pathway and pyroptosis was decreased as well. We also found that the anti-inflammatory effect of ghrelin was associated with inhibition of nuclear factor (NF)-κB activation. Compared with rats in the healthy control group, rats in the ghrelin control group did not show statistically significant changes in histologic examinations, pro-inflammatory cytokines production, or molecules involved in the NLRP3 signaling pathway, which indicated that ghrelin induced no side effects in the animals of our study. Our findings provide more insight into the use of ghrelin as a novel candidate for MS.

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“…Although inflammation is a key component of muscle repair, chronic inflammation results in progressive muscle degeneration and weakness. Similarly to other myopathies, the NLRP3 inflammasome is upregulated in dystrophic mdx muscles and human DMD muscle cells [ 13 , 83 ] ( Figure 3 ). In parallel, expression levels of the components of the NLRP3 inflammasome cascade, such as adaptor protein ASC, pro-caspase-1, pro-IL-1β and mature IL-1β protein, are also elevated in mdx mice myocytes compared to WT mice [ 83 ].…”

Section: Nlrp3 Inflammasome In Musclesmentioning

confidence: 83%

“…Similarly to other myopathies, the NLRP3 inflammasome is upregulated in dystrophic mdx muscles and human DMD muscle cells [ 13 , 83 ] ( Figure 3 ). In parallel, expression levels of the components of the NLRP3 inflammasome cascade, such as adaptor protein ASC, pro-caspase-1, pro-IL-1β and mature IL-1β protein, are also elevated in mdx mice myocytes compared to WT mice [ 83 ]. Upstream receptors of inflammasomes, TLRs, including TLR-1, 2, 3, 4, 7, 8 and 9, are also expressed in a variety of skeletal muscles at different levels in mdx mice [ 84 ].…”

Section: Nlrp3 Inflammasome In Musclesmentioning

confidence: 83%

Aberrant NLRP3 Inflammasome Activation Ignites the Fire of Inflammation in Neuromuscular Diseases

Péladeau

Sandhu

2021

IJMS

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Inflammasomes are molecular hubs that are assembled and activated by a host in response to various microbial and non-microbial stimuli and play a pivotal role in maintaining tissue homeostasis. The NLRP3 is a highly promiscuous inflammasome that is activated by a wide variety of sterile triggers, including misfolded protein aggregates, and drives chronic inflammation via caspase-1-mediated proteolytic cleavage and secretion of proinflammatory cytokines, interleukin-1β and interleukin-18. These cytokines further amplify inflammatory responses by activating various signaling cascades, leading to the recruitment of immune cells and overproduction of proinflammatory cytokines and chemokines, resulting in a vicious cycle of chronic inflammation and tissue damage. Neuromuscular diseases are a heterogeneous group of muscle disorders that involve injury or dysfunction of peripheral nerves, neuromuscular junctions and muscles. A growing body of evidence suggests that dysregulation, impairment or aberrant NLRP3 inflammasome signaling leads to the initiation and exacerbation of pathological processes associated with neuromuscular diseases. In this review, we summarize the available knowledge about the NLRP3 inflammasome in neuromuscular diseases that affect the peripheral nervous system and amyotrophic lateral sclerosis, which affects the central nervous system. In addition, we also examine whether therapeutic targeting of the NLRP3 inflammasome components is a viable approach to alleviating the detrimental phenotype of neuromuscular diseases and improving clinical outcomes.

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Ghrelin improves muscle function in dystrophin-deficient mdx mice by inhibiting NLRP3 inflammasome activation

Cited by 23 publications

References 31 publications

Short-Term ONX-0914 Administration: Performance and Muscle Phenotype in Mdx Mice

Short-Term ONX-0914 Administration: Performance and Muscle Phenotype in Mdx Mice

Ghrelin Attenuates Neuroinflammation and Demyelination in Experimental Autoimmune Encephalomyelitis Involving NLRP3 Inflammasome Signaling Pathway and Pyroptosis

Aberrant NLRP3 Inflammasome Activation Ignites the Fire of Inflammation in Neuromuscular Diseases

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