Pharmacological activation of SERCA ameliorates dystrophic phenotypes in dystrophin-deficient <i>mdx</i> mice

Nogami, Kenichiro; Maruyama, Yusuke; Sakai-Takemura, Fusako; Matsuki, Norio; Elhussieny, Ahmed; Imamura, Michihiro; Miyashita, Satoshi; Ogawa, Megumu; Noguchi, S.; Tamura, Yuki; Kira, Jun‐ichi; Aoki, Yosuke; Takeda, Shin’ichi; Miyagoe-Suzuki, Yuko

doi:10.1093/hmg/ddab100

Cited by 30 publications

(30 citation statements)

References 58 publications

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“…50% in de novo lipogenesis contributes to the dysfunction of sarco/endoplasmic reticulum Ca 2+ -ATPase (SERCA) activity, whereas the recovery of this pathway through the overexpression of lipogenic factors mitigates SERCA function by affecting the composition of the sarcoplasmic reticulum membrane 66 . Of note, pharmacological activation of SERCA was recently demonstrated to provide a promising therapeutic strategy for DMD 67 . Moreover, apart from lipogenic genes, we observed decreased expression of the gene encoding lipid droplet coat protein perilipin 2 ( Plin2 ) in dystrophic livers, similarly to the findings reported by Murphy et al 32 on protein level, further emphasizing the perturbations in lipid homeostasis displayed by dystrophic animals.…”

Section: Discussionmentioning

confidence: 99%

miR-378 affects metabolic disturbances in the mdx model of Duchenne muscular dystrophy

Podkalicka

Mucha

Kaziród

et al. 2022

Sci Rep

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Although Duchenne muscular dystrophy (DMD) primarily affects muscle tissues, the alterations to systemic metabolism manifested in DMD patients contribute to the severe phenotype of this fatal disorder. We propose that microRNA-378a (miR-378) alters carbohydrate and lipid metabolism in dystrophic mdx mice. In our study, we utilized double knockout animals which lacked both dystrophin and miR-378 (mdx/miR-378−/−). RNA sequencing of the liver identified 561 and 194 differentially expressed genes that distinguished mdx versus wild-type (WT) and mdx/miR-378−/− versus mdx counterparts, respectively. Bioinformatics analysis predicted, among others, carbohydrate metabolism disorder in dystrophic mice, as functionally proven by impaired glucose tolerance and insulin sensitivity. The lack of miR-378 in mdx animals mitigated those effects with a faster glucose clearance in a glucose tolerance test (GTT) and normalization of liver glycogen levels. The absence of miR-378 also restored the expression of genes regulating lipid homeostasis, such as Acly, Fasn, Gpam, Pnpla3, and Scd1. In conclusion, we report for the first time that miR-378 loss results in increased systemic metabolism of mdx mice. Together with our previous finding, demonstrating alleviation of the muscle-related symptoms of DMD, we propose that the inhibition of miR-378 may represent a new strategy to attenuate the multifaceted symptoms of DMD.

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Section: Discussionmentioning

confidence: 99%

miR-378 affects metabolic disturbances in the mdx model of Duchenne muscular dystrophy

Podkalicka

Mucha

Kaziród

et al. 2022

Sci Rep

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“…CDN1163 increased ER Ca 2+ content, rescued ERS-induced neuronal death in vitro , and showed significant efficacy in a 6-hydroxydopamine-induced Parkinson’s disease rat model ( Dahl, 2017 ). The dystrophic phenotype of dystrophin-null transgenic mice was ameliorated by CDN1163, which effectively prevented exercise-induced muscle damage and restored mitochondrial function ( Nogami et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Restoration of Sarco/Endoplasmic Reticulum Ca2+-ATPase Activity Functions as a Pivotal Therapeutic Target of Anti-Glutamate-Induced Excitotoxicity to Attenuate Endoplasmic Reticulum Ca2+ Depletion

Zhang

Pang

et al. 2022

Front. Pharmacol.

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Glutamate-induced excitotoxicity is a pathological basis of many acute/chronic neurodegenerative diseases. Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2b) is a membrane-embedded P-type ATPase pump that manages the translocation of calcium ions (Ca2+) from cytosol into the lumen of the endoplasmic reticulum (ER) calcium stores. It participates in a wide range of biological functions in the central nervous system (CNS). However, the role of SERCA2b in glutamate-induced excitotoxicity and its mechanism must be elucidated. Herein, we demonstrate that SERCA2b mutants exacerbate the excitotoxicity of hypo-glutamate stimulation on HT22 cells. In this study, SERCA2b mutants accelerated Ca2+ depletion through loss-of-function (reduced pumping capacity) or gain-of-function (acquired leakage), resulting in ER stress. In addition, the occurrence of ER Ca2+ depletion increased mitochondria-associated membrane formation, which led to mitochondrial Ca2+ overload and dysfunction. Moreover, the enhancement of SERCA2b pumping capacity or inhibition of Ca2+ leakage attenuated Ca2+ depletion and impeded excitotoxicity in response to hypo-glutamate stimulation. In conclusion, SERCA2b mutants exacerbate ER Ca2+-depletion-mediated excitotoxicity in glutamate-sensitive HT22 cells. The mechanism of disruption is mainly related to the heterogeneity of SERCA2b mutation sites. Stabilization of SRECA2b function is a critical therapeutic approach against glutamate-induced excitotoxicity. These data will expand understanding of organelle regulatory networks and facilitate the discovery and creation of drugs against excitatory/inhibitory imbalance in the CNS.

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“…It is well accepted that the absence of dystrophin in the dystrophinopathies, like DMD, triggers skeletal muscle fibre necrosis due to pathological [Ca 2+ ] in regulation (Allen et al ., 2016). Several studies have shown that the skeletal muscle pathology in the dystrophin deficient mdx mouse can be ameliorated by overexpressing or pharmacologically activating the SR Ca 2+ pump, SERCA1 (Goonasekera et al ., 2011; Mázala et al ., 2015; Nogami et al ., 2021). Previously, our group has shown that one consequence of the Actn3KO is a marked increase of SERCA1 protein in fast-twitch skeletal muscle (Head et al ., 2015; Garton et al ., 2018).…”

Section: Discussionmentioning

confidence: 99%

“…We found convincing correlative evidence that the age related protective effect conferred by the absence of α-actinin-3 is due to the reduction in the number and complexity of pathologically branched dystrophic fibres. Additionally, we propose that the mechanism by which the polymorphism R577X induces this protective effect in the dystrophinopathies is due to a switch in the fast-twitch fibres to a more glycolytic metabolism and an increase in the SERCA1 pumps, both of which are known to be protective in the dystrophinopathies (Goonasekera et al ., 2011; Head et al ., 2015; Mázala et al ., 2015; Garton et al ., 2018; Kiriaev et al ., 2021a; Nogami et al ., 2021).…”

Section: Introductionmentioning

confidence: 99%

Loss of α-actinin-3 confers protection from eccentric contraction damage in fast-twitch EDL muscles from aged mdx dystrophic mice by reducing pathological fibre branching

Kiriaev

Houweling

North

et al. 2021

Preprint

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The common null polymorphism (R577X) in the ACTN3 gene is present in over 1.5 billion people worldwide and results in the absence of the protein α-actinin-3 from the Z-discs of fast-twitch skeletal muscle fibres. We have previously reported that this polymorphism is a modifier of dystrophin deficient Duchenne Muscular Dystrophy. To investigate the mechanism underlying this we use a double knockout (dk)Actn3KO/mdx (dKO) mouse model which lacks both dystrophin and sarcomere α-actinin-3. We used dKO mice and mdx dystrophic mice at 12 months (aged) to investigate the correlation between morphological changes to the fast-twitch dKO EDL and the reduction in force deficit produced by an in vitro eccentric contraction protocol. In the aged dKO mouse we found a marked reduction in fibre branching complexity that correlated with protection from eccentric contraction induced force deficit. Complex branches in the aged dKO EDL fibres (28%) were substantially reduced compared to aged mdx EDL fibres (68%) and this correlates with a graded force loss over three eccentric contractions for dKO muscles (~35% after first contraction, ~66% overall) compared to an abrupt drop in mdx upon the first eccentric contraction (~73% after first contraction, ~89% after three contractions). In dKO protection from eccentric contraction damage was linked with a doubling of SERCA1 pump density the EDL. We propose that the increased oxidative metabolism of fast-twitch glycolytic fibres characteristic of the null polymorphism (R577X) and increase in SR Ca2+ pump proteins reduces muscle fibre branching and decreases susceptibility to eccentric injury in the dystrophinopathies.

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Pharmacological activation of SERCA ameliorates dystrophic phenotypes in dystrophin-deficient mdx mice

Cited by 30 publications

References 58 publications

miR-378 affects metabolic disturbances in the mdx model of Duchenne muscular dystrophy

miR-378 affects metabolic disturbances in the mdx model of Duchenne muscular dystrophy

Restoration of Sarco/Endoplasmic Reticulum Ca2+-ATPase Activity Functions as a Pivotal Therapeutic Target of Anti-Glutamate-Induced Excitotoxicity to Attenuate Endoplasmic Reticulum Ca2+ Depletion

Loss of α-actinin-3 confers protection from eccentric contraction damage in fast-twitch EDL muscles from aged mdx dystrophic mice by reducing pathological fibre branching

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