Endoplasmic reticulum stress increases myofiber formation<i>in vitro</i>

Nakanishi, Kazuyoshi; Dohmae, Naoshi; Morishima, Nobuhiro

doi:10.1096/fj.06-6408com

Cited by 104 publications

(123 citation statements)

References 43 publications

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“…By contrast, the processing of other known apoptotic initiator caspases, caspase-1, caspase-2 and caspase-8, was not detectable. We have not excluded a role for the other mouse initiator, caspase-12, which might have importance in this process, given the effect of endoplasmic reticulum (ER) stress on myoblast differentiation (Nakanishi et al, 2007). Second, the processing of caspase-9 suggests autocatalytic proteolysis, consistent with caspase-9 being the initiator.…”

Section: Discussionmentioning

confidence: 97%

A non-apoptotic role for caspase-9 in muscle differentiation

Murray

McMahon

Howley

et al. 2008

Journal of Cell Science

154

117

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Caspases, a family of cysteine proteases most often investigated for their roles in apoptosis, have also been demonstrated to have functions that are vital for the efficient execution of cell differentiation. One such role that has been described is the requirement of caspase-3 for the differentiation of skeletal myoblasts into myotubes but, as yet, the mechanism leading to caspase-3 activation in this case remains elusive. Here, we demonstrate that caspase-9, an initiator caspase in the mitochondrial death pathway, is responsible for the activation of caspase-3 in differentiating C2C12 cells. Reduction of caspase-9 levels, using an shRNA construct, prevented caspase-3 activation and inhibited myoblast fusion. Myosin-heavychain expression, which accompanies myoblastic differentiation, was not caspase-dependent. Overexpression of Bcl-xL, a protein that inhibits caspase-9 activation, had the same effect on muscle differentiation as knockdown of caspase-9. These data suggest that the mitochondrial pathway is required for differentiation; however, the release of cytochrome c or Smac (Diablo) could not be detected, raising the possibility of a novel mechanism of caspase-9 activation during muscle differentiation.

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Section: Discussionmentioning

confidence: 97%

A non-apoptotic role for caspase-9 in muscle differentiation

Murray

McMahon

Howley

et al. 2008

Journal of Cell Science

154

117

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“…However, active caspase-12 is also present in nonapoptotic myogenic cells during development, indicating that it has additional functions beyond initiating apoptosis (56). Several studies suggest a role for caspase-12, -9 and -3 in promoting myoblast differentiation (52,53,55). In contrast, Moresi et al (54) found that increased caspase activity delayed muscle regeneration, by a mechanism independent of caspase-3 and apoptosis, while caspase inhibition improved muscle regeneration.…”

Section: Discussionmentioning

confidence: 99%

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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“…[27][28][29][30][31] In particular, during myogenesis ER stress enhances myoblast differentiation and myofiber formation. 32 Cho et al 31 have shown that ER stress increases during ESC differentiation toward neural cells and that this differentiation is further enhanced through chemical treatment with the ER stress inducers, thapsigargin and tunicamycin. We demonstrated that Nrf3 localizes to the ER at different stages of differentiation ( Figure 6A) and Zhang et al 26 have demonstrated that ER chemical stressors in COS-1 cells activate Nrf3.…”

Section: Discussionmentioning

confidence: 99%

Crucial Role of Nrf3 in Smooth Muscle Cell Differentiation From Stem Cells

Pepe

Xiao²,

Zampetaki³

et al. 2010

Circulation Research

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Rationale: Nuclear factor erythroid 2-related factor (Nrf)3, a member of the cap 'N' collar family of transcription factors that bind to the DNA-antioxidant responsive elements, is involved in reactive oxygen species balancing and in muscle precursor migration during early embryo development. Objective: To investigate the functional role of Nrf3 in smooth muscle cell (SMC) differentiation in vitro and in vivo. Methods and Results: Nrf3 was upregulated significantly following 1 to 8 days of SMC differentiation. Knockdown of Nrf3 resulted in downregulation of smooth muscle specific markers expression, whereas enforced expression of Nrf3 enhanced SMC differentiation in a dose-dependent manner. SMC-specific transcription factor myocardin, but not serum response factor, was significantly upregulated by Nrf3 overexpression. Strikingly, the binding of SRF and myocardin to the promoter of smooth muscle differentiation genes was dramatically increased by Nrf3 overexpression, and Nrf3 can directly bind to the promoters of SMC differentiation genes as demonstrated by chromatin immunoprecipitation assay. Moreover, NADPH-derived reactive oxygen species production during SMC differentiation was further enhanced by Nrf3 overexpression through upregulation of NADPH oxidase and inhibition of antioxidant signaling pathway. In addition, Nrf3 was involved in the endoplasmic reticulum stressor induced SMC differentiation. (SMCs). [1][2][3] Our previous studies showed that growth factor stimulation, 2 mechanical force or extracellular matrix 4 can be used to drive ESC differentiation toward the vascular lineage. We have established an in vitro model for ESC differentiation into SMCs, 3 which involves the choice of extracellular matrix protein collagen IV, 3,5,6 to investigate SMC differentiation more closely. In the adult organism, SMCs have the main physiological function of contracting and controlling the blood vessel tone, diameter, blood pressure and blood flow. In response to vascular injury, SMCs dramatically increase their rate of proliferation, migration and synthetic capacity. 7,8 Atherosclerosis and postangioplasty restenosis, for example, are characterized by the development of an enlarged neointima. 9 The cells responsible for the neointima formation have been identified as not only SMC migrating from the tunica media, 10 but also vascular progenitors that originate from the circulation and the perivascular adventitia, which differentiate into vascular SMCs in the lesion. 11-14 However, the mechanisms involved in SMC differentiation in vitro and in vivo is still poorly understood.In a microarray screen for factors involved in vascular progenitor differentiation, we identified nuclear factor erythroid 2-related factor (Nrf)3 expression to be constantly modulated. Nrf3 is the most recently identified member of the Nrf family and contains a domain homologous to the cap 'N' collar (CNC) transcription factors. 15 The CNC domain is a unique, conserved region, located at the amino-terminus of the bZIP domain. 16 Nrf3 heterodim...

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Endoplasmic reticulum stress increases myofiber formationin vitro

Cited by 104 publications

References 43 publications

A non-apoptotic role for caspase-9 in muscle differentiation

A non-apoptotic role for caspase-9 in muscle differentiation

Caspase-12 ablation preserves muscle function in the mdx mouse

Crucial Role of Nrf3 in Smooth Muscle Cell Differentiation From Stem Cells

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