Activation of Caspase-3 Apoptotic Pathways in Skeletal Muscle Fibers in Laminin α2-Deficient Mice

Mukasa, Takeshi; Momoi, Takashi; Momoi, Mariko Y.

doi:10.1006/bbrc.1999.0829

Cited by 49 publications

(37 citation statements)

References 28 publications

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“…These results suggest that the protection exerted by eEF1A-2/S1 may include a mechanism involved in the regulation of caspase-3 activity. Disruption of the muscle architectural organization triggers the activation of caspase-3, as observed previously in the muscle cell death in muscular dystrophy (32). It will be interesting to analyze the possible analogy between caspase-3 activation in muscular dystrophy and how the expression of both elongation factors eEF1A-1/ EF-1␣ and eEF1A-2/S1 is regulated in this disease state.…”

Section: Discussionmentioning

confidence: 57%

Peptide Elongation Factor eEF1A-2/S1 Expression in Cultured Differentiated Myotubes and Its Protective Effect against Caspase- 3-mediated Apoptosis

Ruest

Marcotte

Wang

2002

Journal of Biological Chemistry

122

109

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Peptide elongation factor eEF1A-2/S1, which shares 92% homology with eEF1A-1/EF-1␣, is exclusively expressed in brain, heart, and skeletal muscle. In these tissues, eEF1A-2/S1 is the only type 1A elongation factor expressed in adulthood because a transition from eEF1A-1/EF-1␣ to eEF1A-2/S1 occurs in early postnatal development. In this article, we report that the expression of eEF1A-2/S1 protein is activated upon myogenic differentiation. Furthermore, we show that upon serum deprivation-induced apoptosis, eEF1A-2/S1 protein disappears and is replaced by its homolog eEF1A-1/EF-1␣ in dying myotubes; cell death is characterized by the activation of caspase-3. In addition, we show that the continuous expression of eEF1A-2/S1 resulting from adenoviral gene transfer protects differentiated myotubes from apoptosis by delaying their death, thus suggesting a prosurvival function for eEF1A-2/S1 in skeletal muscle. In contrast, myotube death is accelerated by the introduction of the homologous gene, eEF1A-1/EF-1␣, whereas cells transfected with antisense eEF1A-1/EF-1␣ are protected from apoptosis. These results demonstrate that the two sister genes, eEF1A-1/EF-1␣ and eEF1A-2/S1, regulate myotube survival with the former exerting prodeath activity and the latter a prosurvival effect.

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Section: Discussionmentioning

confidence: 57%

Peptide Elongation Factor eEF1A-2/S1 Expression in Cultured Differentiated Myotubes and Its Protective Effect against Caspase- 3-mediated Apoptosis

Ruest

Marcotte

Wang

2002

Journal of Biological Chemistry

122

109

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“…Indeed, laminin-α2-deficient skeletal muscles in both humans and mice show relatively abundant signs of muscle cell death by apoptosis (4)(5)(6). To examine the significance of apoptosis in CMD1A pathogenesis, we determined whether pathogenesis in laminin-α2-deficient (Lama2 -/-) mice could be ameliorated by inhibiting apoptosis through either (a) inactivation of the proapoptosis protein Bax or (b) overexpression of the antiapoptosis protein Bcl-2 from a muscle-specific transgene.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of apoptosis improves outcome in a model of congenital muscular dystrophy

Girgenrath

Dominov²,

Kostek³

et al. 2004

J. Clin. Invest.

100

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The most common form of human congenital muscular dystrophy (CMD) is caused by mutations in the laminin-α2 gene. Loss of laminin-α2 function in this autosomal recessive type 1A form of CMD results in neuromuscular dysfunction and, often, early death. Laminin-α2-deficient skeletal muscles in both humans and mice show signs of muscle cell death by apoptosis. To examine the significance of apoptosis in CMD1A pathogenesis, we determined whether pathogenesis in laminin-α2-deficient (Lama2 -/-) mice could be ameliorated by inhibiting apoptosis through either (a) inactivation of the proapoptosis protein Bax or (b) overexpression of the antiapoptosis protein Bcl-2 from a muscle-specific transgene. We found that both of these genetic interventions produced a several-fold increase in the lifespan of Lama2 -/-mice. Bax inactivation also improved postnatal growth rate and myofiber histology and decreased fixed contractures of Lama2 -/-mice. Thus, Bcl-2 family-mediated apoptosis contributes significantly to pathogenesis in the mouse model of CMD1A, and antiapoptosis therapy may be a possible route to amelioration of neuromuscular dysfunction due to laminin-α2 deficiency in humans.

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“…Delayed neuronal death occurs a few days after the ischemic insult, but which cascade necrosis or apoptosis is mainly involved remains uncertain. Ultrastructural data have shown that the postischemic CA1 neurons display necrotic rather than apoptotic features (Colbourne et al, 1999;Tsukada et al, 2001;Zhao et al, 2002), while a number of reports indicate that apoptosis contributes to ischemic neuronal death (MacManus et al, 1993;Nitatori et al, 1995;Vexler et al, 1997;MacManus and Linnik, 1997;Chen et al, 1998;Mukasa et al, 1999). Accordingly, there is no consensus as to what is the final effector of CA1 neuronal death.…”

Section: Introductionmentioning

confidence: 99%

Sustained calpain activation associated with lysosomal rupture executes necrosis of the postischemic CA1 neurons in primates

et al. 2003

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ABSTRACT:Because of the paucity of primate experimental models, the precise molecular mechanism of ischemic neuronal death remains unknown in humans. This study focused on nonhuman primates to determine which cascade necrosis or apoptosis is predominantly involved in the development of delayed (day 5) neuronal death in the hippocampal CA1 sector undergoing 20 min ischemia. We investigated expression, activation, and/or translocation of -calpain, lysosome-associated membrane protein-1 (LAMP-1), caspase-3, and caspase-activated DNase (CAD), as well as morphology of the postischemic CA1 neurons and DNA electrophoresis pattern. Immunoblotting showed sustained (immediately after ischemia until day 5) and maximal (day 3) activation of -calpain. The immunoreactivity of activated -calpain became remarkable as coarse granules at lysosomes on day 2, while it translocated throughout the perikarya on day 3. The immunoreactivity of LAMP-1 also showed a dynamic and concomitant translocation that was maximal on days 2-3, indicating calpain-mediated disruption of the lysosomal membrane after ischemia. In contrast, immunoblotting demonstrated essentially no increase in the activated caspase-3 at any time points after ischemia, despite upregulation of pro-caspase-3. Although expression of CAD was slightly upregulated on day 1 or 2, or both, it was much less compared with lymph node or intestine tissues. Furthermore, light and electron microscopy showed eosinophilic coagulation necrosis and membrane disruption without apoptotic body formation, while DNA electrophoresis did not show a ladder pattern, but rather a smear pattern. Sustained calpain activation and the resultant lysosomal rupture, rather than CAD-mediated apoptosis, may cause ischemic neuronal necrosis in primates.

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Activation of Caspase-3 Apoptotic Pathways in Skeletal Muscle Fibers in Laminin α2-Deficient Mice

Cited by 49 publications

References 28 publications

Peptide Elongation Factor eEF1A-2/S1 Expression in Cultured Differentiated Myotubes and Its Protective Effect against Caspase- 3-mediated Apoptosis

Peptide Elongation Factor eEF1A-2/S1 Expression in Cultured Differentiated Myotubes and Its Protective Effect against Caspase- 3-mediated Apoptosis

Inhibition of apoptosis improves outcome in a model of congenital muscular dystrophy

Sustained calpain activation associated with lysosomal rupture executes necrosis of the postischemic CA1 neurons in primates

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