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Skeletal Muscle Differentiation Evokes Endogenous XIAP to Restrict the Apoptotic Pathway

Myotube apoptosis occurs normally during muscle development and aging but it can lead to destruction of skeletal muscle in neuromuscular diseases. Therefore, understanding how myotube apoptosis is regulated is important for developing novel strategies for treatment of muscle loss. We investigated th...

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Autores principales: Smith, Michelle I., Huang, Yolanda Y., Deshmukh, Mohanish
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2658743/
https://www.ncbi.nlm.nih.gov/pubmed/19333375
http://dx.doi.org/10.1371/journal.pone.0005097
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author Smith, Michelle I.
Huang, Yolanda Y.
Deshmukh, Mohanish
author_facet Smith, Michelle I.
Huang, Yolanda Y.
Deshmukh, Mohanish
author_sort Smith, Michelle I.
collection PubMed
description Myotube apoptosis occurs normally during muscle development and aging but it can lead to destruction of skeletal muscle in neuromuscular diseases. Therefore, understanding how myotube apoptosis is regulated is important for developing novel strategies for treatment of muscle loss. We investigated the regulation of apoptosis in skeletal muscle and report a striking increase in resistance to apoptosis following differentiation. We find mitotic C2C12 cells (myoblast-like cells) are sensitive to cytosolic cytochrome c microinjection. However, differentiated C2C12 cells (myotube-like cells) and primary myotubes are markedly resistant. This resistance is due to endogenous X-linked inhibitor of apoptotic protein (XIAP). Importantly, the selective difference in the ability of XIAP to block myotube but not myoblast apoptosis is not due to a change in XIAP but rather a decrease in Apaf-1 expression. This decrease in Apaf-1 links XIAP to caspase activation and death. Our findings suggest that in order for myotubes to die, they may degrade XIAP, functionally inactivate XIAP or upregulate Apaf-1. Importantly, we identify a role for endogenous Smac in overcoming XIAP to allow myotube death. However, in postmitotic cardiomyocytes, where XIAP also restricts apoptosis, endogenous Smac was not capable of overcoming XIAP to cause death. These results show that as skeletal muscle differentiate, they become resistant to apoptosis because of the ability of XIAP to regulate caspase activation. The increased restriction of apoptosis in myotubes is presumably important to ensure the long term survival of these postmitotic cells as they play a vital role in the physiology of organisms.
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spelling pubmed-26587432009-03-31 Skeletal Muscle Differentiation Evokes Endogenous XIAP to Restrict the Apoptotic Pathway Smith, Michelle I. Huang, Yolanda Y. Deshmukh, Mohanish PLoS One Research Article Myotube apoptosis occurs normally during muscle development and aging but it can lead to destruction of skeletal muscle in neuromuscular diseases. Therefore, understanding how myotube apoptosis is regulated is important for developing novel strategies for treatment of muscle loss. We investigated the regulation of apoptosis in skeletal muscle and report a striking increase in resistance to apoptosis following differentiation. We find mitotic C2C12 cells (myoblast-like cells) are sensitive to cytosolic cytochrome c microinjection. However, differentiated C2C12 cells (myotube-like cells) and primary myotubes are markedly resistant. This resistance is due to endogenous X-linked inhibitor of apoptotic protein (XIAP). Importantly, the selective difference in the ability of XIAP to block myotube but not myoblast apoptosis is not due to a change in XIAP but rather a decrease in Apaf-1 expression. This decrease in Apaf-1 links XIAP to caspase activation and death. Our findings suggest that in order for myotubes to die, they may degrade XIAP, functionally inactivate XIAP or upregulate Apaf-1. Importantly, we identify a role for endogenous Smac in overcoming XIAP to allow myotube death. However, in postmitotic cardiomyocytes, where XIAP also restricts apoptosis, endogenous Smac was not capable of overcoming XIAP to cause death. These results show that as skeletal muscle differentiate, they become resistant to apoptosis because of the ability of XIAP to regulate caspase activation. The increased restriction of apoptosis in myotubes is presumably important to ensure the long term survival of these postmitotic cells as they play a vital role in the physiology of organisms. Public Library of Science 2009-03-31 /pmc/articles/PMC2658743/ /pubmed/19333375 http://dx.doi.org/10.1371/journal.pone.0005097 Text en Smith et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Smith, Michelle I.
Huang, Yolanda Y.
Deshmukh, Mohanish
Skeletal Muscle Differentiation Evokes Endogenous XIAP to Restrict the Apoptotic Pathway
title Skeletal Muscle Differentiation Evokes Endogenous XIAP to Restrict the Apoptotic Pathway
title_full Skeletal Muscle Differentiation Evokes Endogenous XIAP to Restrict the Apoptotic Pathway
title_fullStr Skeletal Muscle Differentiation Evokes Endogenous XIAP to Restrict the Apoptotic Pathway
title_full_unstemmed Skeletal Muscle Differentiation Evokes Endogenous XIAP to Restrict the Apoptotic Pathway
title_short Skeletal Muscle Differentiation Evokes Endogenous XIAP to Restrict the Apoptotic Pathway
title_sort skeletal muscle differentiation evokes endogenous xiap to restrict the apoptotic pathway
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2658743/
https://www.ncbi.nlm.nih.gov/pubmed/19333375
http://dx.doi.org/10.1371/journal.pone.0005097
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