Activation of caspase 3, 9, 12, and Bax in masseter muscle of mdx mice during necrosis

Honda, A; Abe, Shinichi; Hiroki, Emi; Honda, Hideo; Iwanuma, Osamu; Yanagisawa, Nobuaki; Ide, Yoshinobu

doi:10.1007/s10974-007-9122-9

Cited by 21 publications

(19 citation statements)

References 19 publications

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“…Importantly, BiP and cleaved caspase-4 were also elevated in muscle samples from DMD patients. The increase in caspase-12 is consistent with a previous study that found increased caspase-12 expression in the masseter of young mdx mice (38). Increased P-JNK, which is not specific to ER stress, has also been previously observed in 8-week-old mdx TA muscles (39) and 5-month-old mdx hearts (40).…”

Section: Discussionsupporting

confidence: 92%

Caspase-12 ablation preserves muscle function in the mdx mouse

Moorwood

Barton

2014

Human Molecular Genetics

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Duchenne muscular dystrophy (DMD) is a devastating muscle wasting disease caused by mutations in dystrophin. Several downstream consequences of dystrophin deficiency are triggers of endoplasmic reticulum (ER) stress, including loss of calcium homeostasis, hypoxia and oxidative stress. During ER stress, misfolded proteins accumulate in the ER lumen and the unfolded protein response (UPR) is triggered, leading to adaptation or apoptosis. We hypothesized that ER stress is heightened in dystrophic muscles and contributes to the pathology of DMD. We observed increases in the ER stress markers BiP and cleaved caspase-4 in DMD patient biopsies, compared with controls, and an increase in multiple UPR pathways in muscles of the dystrophin-deficient mdx mouse. We then crossed mdx mice with mice null for caspase-12, the murine equivalent of human caspase-4, which are resistant to ER stress. We found that deleting caspase-12 preserved mdx muscle function, resulting in a 75% recovery of both specific force generation and resistance to eccentric contractions. The compensatory hypertrophy normally found in mdx muscles was normalized in the absence of caspase-12; this was found to be due to decreased fibre sizes, and not to a fibre type shift or a decrease in fibrosis. Fibre central nucleation was not significantly altered in the absence of caspase-12, but muscle fibre degeneration found in the mdx mouse was reduced almost to wild-type levels. In conclusion, we have identified heightened ER stress and abnormal UPR signalling as novel contributors to the dystrophic phenotype. Caspase-4 is therefore a potential therapeutic target for DMD.

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Section: Discussionsupporting

confidence: 92%

Caspase-12 ablation preserves muscle function in the mdx mouse

Moorwood

Barton

2014

Human Molecular Genetics

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“…In contrast, B10 mice showed normal skeletal muscle and immunolocalization of dystrophin. It has been reported that in somite-derived muscles of the extremities, muscle necrosis begins 2 weeks after birth, immediately followed by regeneration, and the majority of necrotic muscles are regenerated by 4 weeks after birth (Dangain and Vrbova, 1984;DiMario et al, 1991;Attal et al, 2000;Honda et al, 2007;Abe et al, 2007). We observed a similar pattern in Mdx mice, though over a different period of time, with complete muscle regeneration at 9 weeks.…”

Section: Discussionsupporting

confidence: 78%

Expression of Myostatin and Follistatin inMdxMice, an Animal Model for Muscular Dystrophy

et al. 2009

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Follistatin is a functional antagonist of several members of the TGF-β family of secreted signaling factors, including myostatin, the most powerful inhibitor of muscle growth characterized to date. Myostatin inhibition offers a novel therapeutic strategy for muscular dystrophy by restoring skeletal muscle mass and suppressing the progression of muscle degeneration. To assess the potential benefits of follistatin in treating muscle degenerative diseases, we examined the expression of myostatin and follistatin in Mdx mice, a model for Duchenne muscular dystrophy, and in B10 mice as a control. Our results demonstrated a temporary and coincident expression of follistatin and myostatin in both mouse strains, but this expression was significantly higher in Mdx mice than in B10 mice. The maximum expression of follistatin and myostatin in the presence of restoring necrotic muscle was detected 4 weeks after birth in Mdx mice. Interestingly, during the stage of complete regeneration, the absence of myostatin and follistatin proteins and a marked decrease in the expression of both genes were observed 9 weeks after birth in both mouse strains. These findings suggest that follistatin not only blocks myostatin but also allows other activators to function in muscle development, emphasizing that follistatin could be a very potent molecule in combating muscle loss during dystrophies and muscle ageing, disuse, or denervation.

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“…Expression levels of caspase-3, caspase-9, and Bax expression levels have been shown to be significantly upregulated in the muscle of mdx mice [58]. An imbalance between the production and degeneration of myocytes, exacerbated by increased apoptosis and decreased regenerative capacity leads to atrophy in the skeletal muscle of mdx mice [59].…”

Section: Discussionmentioning

confidence: 99%

Characterization and Functional Analysis of Extracellular Vesicles and Muscle-Abundant miRNAs (miR-1, miR-133a, and miR-206) in C2C12 Myocytes and mdx Mice

et al. 2016

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Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disorder. Here, we show that the CD63 antigen, which is located on the surface of extracellular vesicles (EVs), is associated with increased levels of muscle-abundant miRNAs, namely myomiRs miR-1, miR-133a, and miR-206, in the sera of DMD patients and mdx mice. Furthermore, the release of EVs from the murine myoblast C2C12 cell line was found to be modulated by intracellular ceramide levels in a Ca2+-dependent manner. Next, to investigate the effects of EVs on cell survival, C2C12 myoblasts and myotubes were cultured with EVs from the sera of mdx mice or C2C12 cells overexpressing myomiRs in presence of cellular stresses. Both the exposure of C2C12 myoblasts and myotubes to EVs from the serum of mdx mice, and the overexpression of miR-133a in C2C12 cells in presence of cellular stress resulted in a significant decrease in cell death. Finally, to assess whether miRNAs regulate skeletal muscle regeneration in vivo, we intraperitoneally injected GW4869 (an inhibitor of exosome secretion) into mdx mice for 5 and 10 days. Levels of miRNAs and creatine kinase in the serum of GW4869-treated mdx mice were significantly downregulated compared with those of controls. The tibialis anterior muscles of the GW4869-treated mdx mice showed a robust decrease in Evans blue dye uptake. Collectively, these results indicate that EVs and myomiRs might protect the skeletal muscle of mdx mice from degeneration.

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Activation of caspase 3, 9, 12, and Bax in masseter muscle of mdx mice during necrosis

Cited by 21 publications

References 19 publications

Caspase-12 ablation preserves muscle function in the mdx mouse

Caspase-12 ablation preserves muscle function in the mdx mouse

Expression of Myostatin and Follistatin inMdxMice, an Animal Model for Muscular Dystrophy

Characterization and Functional Analysis of Extracellular Vesicles and Muscle-Abundant miRNAs (miR-1, miR-133a, and miR-206) in C2C12 Myocytes and mdx Mice

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