Lack of CFTR in Skeletal Muscle Predisposes to Muscle Wasting and Diaphragm Muscle Pump Failure in Cystic Fibrosis Mice
| Autor: | Danuta Radzioch, Gawiyou Danialou, John W. Hanrahan, Christina Haston, Maziar Divangahi, Basil J. Petrof, Sheila Ernest, Alain S. Comtois, Alexandre Demoule, Haouaria Balghi, Renaud Robert |
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| Rok vydání: | 2009 |
| Předmět: |
Cancer Research
Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator Gene Expression Respiratory Medicine/Respiratory Infections Physiology/Muscle and Connective Tissue Mice 0302 clinical medicine Myocyte Cells Cultured Genetics (clinical) Mice Knockout 2. Zero hunger Mice Inbred BALB C 0303 health sciences Muscle Weakness Myogenesis Cystic fibrosis transmembrane conductance regulator Muscle atrophy 3. Good health medicine.anatomical_structure Physiology/Respiratory Physiology Cytokines Physiology/Immune Response medicine.symptom ITGA7 Research Article medicine.medical_specialty lcsh:QH426-470 Diaphragm Biology 03 medical and health sciences Internal medicine Respiratory Medicine/Respiratory Failure Genetics medicine Respiratory muscle Animals Humans Genetic Predisposition to Disease Muscle Skeletal Molecular Biology Ecology Evolution Behavior and Systematics 030304 developmental biology Muscle weakness Skeletal muscle Mice Inbred C57BL lcsh:Genetics Disease Models Animal Endocrinology Genetics and Genomics/Disease Models 030228 respiratory system biology.protein Calcium |
| Zdroj: | PLoS Genetics PLoS Genetics, Vol 5, Iss 7, p e1000586 (2009) |
| ISSN: | 1553-7404 |
| Popis: | 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. Author Summary Cystic fibrosis is an autosomal recessive disorder caused by mutations of the CF transmembrane conductance regulator (CFTR), which acts as a chloride channel and also participates in the regulation of other ions and proteins. In most CF patients, the clinical course is dominated by lung disease and recurrent pulmonary bacterial infections. Many CF patients also have significant skeletal muscle wasting and weakness, and this can affect the most essential breathing muscle, the diaphragm. Although muscle wasting in CF has generally been attributed to factors such as reduced physical activity and poor nutrition, our study reveals an intrinsic defect of skeletal muscle function caused by the lack of CFTR. Hence, we show that CFTR is normally found in skeletal muscle fibers of humans and mice. In CF muscle cells lacking CFTR, abnormal elevations of calcium and inflammatory gene expression are found. In addition, during pulmonary infections, diaphragm muscles lacking CFTR show greater weakness and induction of genes which cause muscle atrophy. These findings extend our understanding of the factors leading to exercise limitation and disability in CF and also have implications for the pathogenesis of respiratory muscle failure in CF patients during lung infections. |
| Databáze: | OpenAIRE |
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