Cargando…
Lack of CFTR in Skeletal Muscle Predisposes to Muscle Wasting and Diaphragm Muscle Pump Failure in Cystic Fibrosis Mice
Cystic fibrosis (CF) patients often have reduced mass and strength of skeletal muscles, including the diaphragm, the primary muscle of respiration. Here we show that lack of the CF transmembrane conductance regulator (CFTR) plays an intrinsic role in skeletal muscle atrophy and dysfunction. In norma...
Autores principales: | , , , , , , , , , , |
---|---|
Formato: | Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2009
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2709446/ https://www.ncbi.nlm.nih.gov/pubmed/19649303 http://dx.doi.org/10.1371/journal.pgen.1000586 |
_version_ | 1782169294498430976 |
---|---|
author | Divangahi, Maziar Balghi, Haouaria Danialou, Gawiyou Comtois, Alain S. Demoule, Alexandre Ernest, Sheila Haston, Christina Robert, Renaud Hanrahan, John W. Radzioch, Danuta Petrof, Basil J. |
author_facet | Divangahi, Maziar Balghi, Haouaria Danialou, Gawiyou Comtois, Alain S. Demoule, Alexandre Ernest, Sheila Haston, Christina Robert, Renaud Hanrahan, John W. Radzioch, Danuta Petrof, Basil J. |
author_sort | Divangahi, Maziar |
collection | PubMed |
description | Cystic fibrosis (CF) patients often have reduced mass and strength of skeletal muscles, including the diaphragm, the primary muscle of respiration. Here we show that lack of the CF transmembrane conductance regulator (CFTR) plays an intrinsic role in skeletal muscle atrophy and dysfunction. In normal murine and human skeletal muscle, CFTR is expressed and co-localized with sarcoplasmic reticulum-associated proteins. CFTR–deficient myotubes exhibit augmented levels of intracellular calcium after KCl-induced depolarization, and exposure to an inflammatory milieu induces excessive NF-kB translocation and cytokine/chemokine gene upregulation. To determine the effects of an inflammatory environment in vivo, sustained pulmonary infection with Pseudomonas aeruginosa was produced, and under these conditions diaphragmatic force-generating capacity is selectively reduced in Cftr (−/−) mice. This is associated with exaggerated pro-inflammatory cytokine expression as well as upregulation of the E3 ubiquitin ligases (MuRF1 and atrogin-1) involved in muscle atrophy. We conclude that an intrinsic alteration of function is linked to the absence of CFTR from skeletal muscle, leading to dysregulated calcium homeostasis, augmented inflammatory/atrophic gene expression signatures, and increased diaphragmatic weakness during pulmonary infection. These findings reveal a previously unrecognized role for CFTR in skeletal muscle function that may have major implications for the pathogenesis of cachexia and respiratory muscle pump failure in CF patients. |
format | Text |
id | pubmed-2709446 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2009 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-27094462009-08-01 Lack of CFTR in Skeletal Muscle Predisposes to Muscle Wasting and Diaphragm Muscle Pump Failure in Cystic Fibrosis Mice Divangahi, Maziar Balghi, Haouaria Danialou, Gawiyou Comtois, Alain S. Demoule, Alexandre Ernest, Sheila Haston, Christina Robert, Renaud Hanrahan, John W. Radzioch, Danuta Petrof, Basil J. PLoS Genet Research Article Cystic fibrosis (CF) patients often have reduced mass and strength of skeletal muscles, including the diaphragm, the primary muscle of respiration. Here we show that lack of the CF transmembrane conductance regulator (CFTR) plays an intrinsic role in skeletal muscle atrophy and dysfunction. In normal murine and human skeletal muscle, CFTR is expressed and co-localized with sarcoplasmic reticulum-associated proteins. CFTR–deficient myotubes exhibit augmented levels of intracellular calcium after KCl-induced depolarization, and exposure to an inflammatory milieu induces excessive NF-kB translocation and cytokine/chemokine gene upregulation. To determine the effects of an inflammatory environment in vivo, sustained pulmonary infection with Pseudomonas aeruginosa was produced, and under these conditions diaphragmatic force-generating capacity is selectively reduced in Cftr (−/−) mice. This is associated with exaggerated pro-inflammatory cytokine expression as well as upregulation of the E3 ubiquitin ligases (MuRF1 and atrogin-1) involved in muscle atrophy. We conclude that an intrinsic alteration of function is linked to the absence of CFTR from skeletal muscle, leading to dysregulated calcium homeostasis, augmented inflammatory/atrophic gene expression signatures, and increased diaphragmatic weakness during pulmonary infection. These findings reveal a previously unrecognized role for CFTR in skeletal muscle function that may have major implications for the pathogenesis of cachexia and respiratory muscle pump failure in CF patients. Public Library of Science 2009-07-31 /pmc/articles/PMC2709446/ /pubmed/19649303 http://dx.doi.org/10.1371/journal.pgen.1000586 Text en Divangahi 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 Divangahi, Maziar Balghi, Haouaria Danialou, Gawiyou Comtois, Alain S. Demoule, Alexandre Ernest, Sheila Haston, Christina Robert, Renaud Hanrahan, John W. Radzioch, Danuta Petrof, Basil J. Lack of CFTR in Skeletal Muscle Predisposes to Muscle Wasting and Diaphragm Muscle Pump Failure in Cystic Fibrosis Mice |
title | Lack of CFTR in Skeletal Muscle Predisposes to Muscle Wasting and Diaphragm Muscle Pump Failure in Cystic Fibrosis Mice |
title_full | Lack of CFTR in Skeletal Muscle Predisposes to Muscle Wasting and Diaphragm Muscle Pump Failure in Cystic Fibrosis Mice |
title_fullStr | Lack of CFTR in Skeletal Muscle Predisposes to Muscle Wasting and Diaphragm Muscle Pump Failure in Cystic Fibrosis Mice |
title_full_unstemmed | Lack of CFTR in Skeletal Muscle Predisposes to Muscle Wasting and Diaphragm Muscle Pump Failure in Cystic Fibrosis Mice |
title_short | Lack of CFTR in Skeletal Muscle Predisposes to Muscle Wasting and Diaphragm Muscle Pump Failure in Cystic Fibrosis Mice |
title_sort | lack of cftr in skeletal muscle predisposes to muscle wasting and diaphragm muscle pump failure in cystic fibrosis mice |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2709446/ https://www.ncbi.nlm.nih.gov/pubmed/19649303 http://dx.doi.org/10.1371/journal.pgen.1000586 |
work_keys_str_mv | AT divangahimaziar lackofcftrinskeletalmusclepredisposestomusclewastinganddiaphragmmusclepumpfailureincysticfibrosismice AT balghihaouaria lackofcftrinskeletalmusclepredisposestomusclewastinganddiaphragmmusclepumpfailureincysticfibrosismice AT danialougawiyou lackofcftrinskeletalmusclepredisposestomusclewastinganddiaphragmmusclepumpfailureincysticfibrosismice AT comtoisalains lackofcftrinskeletalmusclepredisposestomusclewastinganddiaphragmmusclepumpfailureincysticfibrosismice AT demoulealexandre lackofcftrinskeletalmusclepredisposestomusclewastinganddiaphragmmusclepumpfailureincysticfibrosismice AT ernestsheila lackofcftrinskeletalmusclepredisposestomusclewastinganddiaphragmmusclepumpfailureincysticfibrosismice AT hastonchristina lackofcftrinskeletalmusclepredisposestomusclewastinganddiaphragmmusclepumpfailureincysticfibrosismice AT robertrenaud lackofcftrinskeletalmusclepredisposestomusclewastinganddiaphragmmusclepumpfailureincysticfibrosismice AT hanrahanjohnw lackofcftrinskeletalmusclepredisposestomusclewastinganddiaphragmmusclepumpfailureincysticfibrosismice AT radziochdanuta lackofcftrinskeletalmusclepredisposestomusclewastinganddiaphragmmusclepumpfailureincysticfibrosismice AT petrofbasilj lackofcftrinskeletalmusclepredisposestomusclewastinganddiaphragmmusclepumpfailureincysticfibrosismice |