The nSMase2/Smpd3 gene modulates the severity of muscular dystrophy and the emotional stress response in mdx mice

Matsuzaka, Yasunari; Tanihata, Jun; Ooshima, Yoshiko; Yamada, Daisuke; Sekiguchi, Masayuki; Miyatake, Shouta; Aoki, Yosuke; Terumitsu, Mika; Yashiro, Ryu; Komaki, Hirofumi; Ishiyama, Akihiko; Oya, Yasushi; Inoue, Yukiko; Inoue, Tohru; Takeda, Shin’ichi; Hashido, Kazuo

doi:10.1186/s12916-020-01805-5

Cited by 13 publications

(12 citation statements)

References 62 publications

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“…A recent paper from Gartz et al (2020), showed that GW4869 treatment to reduce exosome release (by neutral sphingomyelinase [nSMase] inhibition) in mdx mice (a popular model of DMD) was protective against cardiac stress, which authors attributed to miR cargo. In line with this, Matsuzaka et al (2020) showed that ablation of nSMase2/Smpd3 gene in mice with a mdx background decreased muscle inflammation and improved functionality.…”

Section:  Skeletal Musclesupporting

confidence: 57%

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In sickness and in health: The functional role of extracellular vesicles in physiology and pathology in vivo

Yates

Pink

Erdbrügger

et al. 2022

J of Extracellular Vesicle

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It is clear from Part I of this series that extracellular vesicles (EVs) play a critical role in maintaining the homeostasis of most, if not all, normal physiological systems. However, the majority of our knowledge about EV signalling has come from studying them in disease. Indeed, EVs have consistently been associated with propagating disease pathophysiology. The analysis of EVs in biofluids, obtained in the clinic, has been an essential of the work to improve our understanding of their role in disease. However, to interfere with EV signalling for therapeutic gain, a more fundamental understanding of the mechanisms by which they contribute to pathogenic processes is required. Only by discovering how the EV populations in different biofluids change—size, number, and physicochemical composition—in clinical samples, may we then begin to unravel their functional roles in translational models in vitro and in vivo, which can then feedback to the clinic. In Part II of this review series, the functional role of EVs in pathology and disease will be discussed, with a focus on in vivo evidence and their potential to be used as both biomarkers and points of therapeutic intervention.

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Section:  Skeletal Musclesupporting

confidence: 57%

“…In line with this, Matsuzaka et al. ( 2020 ) showed that ablation of nSMase2/Smpd3 gene in mice with a mdx background decreased muscle inflammation and improved functionality.…”

Section: Musculoskeletal Pathologymentioning

confidence: 76%

In sickness and in health: The functional role of extracellular vesicles in physiology and pathology in vivo

Yates

Pink

Erdbrügger

et al. 2022

J of Extracellular Vesicle

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“…Rescuing the behavioral stress response of mdx mice is thought to occur through normalization of GABAergic receptor expression, 8 brain-derived neurotrophic factor 19 and skeletal muscle-driven regulation of blood pressure. 11 Our metabolomic profiling data from stress-resistant and stress-sensitive male and female mdx mice confirms the role of hemodynamics in the behavioral stress response of mdx mice.…”

Section: Discussionmentioning

confidence: 99%

“…The hyper-exaggerated stress response of mdx mice manifests as acute physical inactivity after scruff restraint, forced downhill treadmill exercise or social defeat (severe psychosocial stress in rodents based on dominance and social hierarchy in males). 11,13,17,18 The stress response is associated with altered spatial localization of GABAergic receptors in the brain, 8 expression of the nSMase2/ Smpd3 gene 19 and hyper-activation of the hypothalamicpituitary-adrenal (HPA) axis. 11,13 However, there is now evidence indicating scruff restraint and social defeatinduced physical inactivity in mdx mice is linked to a loss in mean arterial blood pressure with concurrent tachycardia, a perturbation that can result in a 70% mortality rate after social defeat.…”

Section: Introductionmentioning

confidence: 99%

Sensitivity to behavioral stress impacts disease pathogenesis in dystrophin‐deficient mice

et al. 2021

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Mutation to the gene encoding dystrophin can cause Duchenne muscular dystrophy (DMD) and increase the sensitivity to stress in vertebrate species, including the mdx mouse model of DMD. Behavioral stressors can exacerbate some dystrophinopathy phenotypes of mdx skeletal muscle and cause hypotension-induced death. However, we have discovered that a subpopulation of mdx mice present with a wildtype-like response to mild (forced downhill treadmill exercise) and moderate (scruff restraint) behavioral stressors. These "stress-resistant" mdx mice are more physically active, capable of super-activating the hypothalamic-pituitaryadrenal and renin-angiotensin-aldosterone pathways following behavioral stress and they express greater levels of mineralocorticoid and glucocorticoid receptors in striated muscle relative to "stress-sensitive" mdx mice. Stress-resistant mdx mice also presented with a less severe striated muscle histopathology and greater exercise and skeletal muscle oxidative capacity at rest. Most interestingly, female mdx mice were more physically active following behavioral stressors compared to male mdx mice; a response abolished after ovariectomy and rescued with estradiol. We demonstrate that the response to behavioral stress greatly impacts disease severity in mdx mice suggesting the management of stress in patients with DMD be considered as a therapeutic approach to ameliorate disease progression.

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“…Thus, to elucidate the relationship between the release of myomiRs via EV and DMD pathogenesis, GW4869 (an inhibitor of nSMase2/Smpd3) was administered to mdx mice. It has been shown that the inhibition of nSMase2/Smpd3 enzymatic activity ameliorates skeletal muscles of muscular dystrophy in mdx mice, in turn, inhibits ceramide synthesis [150]. However, there are problems with the GW4869 inhibitor, in that it has effects on other nSMase2/Smpd3 family members and relatively short-term inhibitory effects.…”

Section: Neutral Sphingomyelinase 2/sphingomyelin Phosphodiesterase 3 (Nsmase2/smpd3) and Dmdmentioning

confidence: 99%

Therapeutic Application of Extracellular Vesicles-Capsulated Adeno-Associated Virus Vector via nSMase2/Smpd3, Satellite, and Immune Cells in Duchenne Muscular Dystrophy

Matsuzaka

Hirai

Hashido

et al. 2022

IJMS

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Duchenne muscular dystrophy (DMD) is caused by loss-of-function mutations in the dystrophin gene on chromosome Xp21. Disruption of the dystrophin–glycoprotein complex (DGC) on the cell membrane causes cytosolic Ca2+ influx, resulting in protease activation, mitochondrial dysfunction, and progressive myofiber degeneration, leading to muscle wasting and fragility. In addition to the function of dystrophin in the structural integrity of myofibers, a novel function of asymmetric cell division in muscular stem cells (satellite cells) has been reported. Therefore, it has been suggested that myofiber instability may not be the only cause of dystrophic degeneration, but rather that the phenotype might be caused by multiple factors, including stem cell and myofiber functions. Furthermore, it has been focused functional regulation of satellite cells by intracellular communication of extracellular vesicles (EVs) in DMD pathology. Recently, a novel molecular mechanism of DMD pathogenesis—circulating RNA molecules—has been revealed through the study of target pathways modulated by the Neutral sphingomyelinase2/Neutral sphingomyelinase3 (nSMase2/Smpd3) protein. In addition, adeno-associated virus (AAV) has been clinically applied for DMD therapy owing to the safety and long-term expression of transduction genes. Furthermore, the EV-capsulated AAV vector (EV-AAV) has been shown to be a useful tool for the intervention of DMD, because of the high efficacy of the transgene and avoidance of neutralizing antibodies. Thus, we review application of AAV and EV-AAV vectors for DMD as novel therapeutic strategy.

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The nSMase2/Smpd3 gene modulates the severity of muscular dystrophy and the emotional stress response in mdx mice

Cited by 13 publications

References 62 publications

In sickness and in health: The functional role of extracellular vesicles in physiology and pathology in vivo

In sickness and in health: The functional role of extracellular vesicles in physiology and pathology in vivo

Sensitivity to behavioral stress impacts disease pathogenesis in dystrophin‐deficient mice

Therapeutic Application of Extracellular Vesicles-Capsulated Adeno-Associated Virus Vector via nSMase2/Smpd3, Satellite, and Immune Cells in Duchenne Muscular Dystrophy

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