| Autor: |
Gusev E; Meakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, Quebec, Canada.; Translational Research in Respiratory Diseases Program, McGill University Health Center and Research Institute, Montreal, Quebec, Canada., Liang F; Meakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, Quebec, Canada.; Translational Research in Respiratory Diseases Program, McGill University Health Center and Research Institute, Montreal, Quebec, Canada., Bhattarai S; Meakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, Quebec, Canada.; Translational Research in Respiratory Diseases Program, McGill University Health Center and Research Institute, Montreal, Quebec, Canada., Broering FE; Meakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, Quebec, Canada.; Translational Research in Respiratory Diseases Program, McGill University Health Center and Research Institute, Montreal, Quebec, Canada., Leduc-Gaudet JP; Meakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, Quebec, Canada.; Translational Research in Respiratory Diseases Program, McGill University Health Center and Research Institute, Montreal, Quebec, Canada., Hussain SN; Meakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, Quebec, Canada.; Translational Research in Respiratory Diseases Program, McGill University Health Center and Research Institute, Montreal, Quebec, Canada., Radzioch D; Department of Human Genetics, McGill University, Montreal, Quebec, Canada.; Infectious Diseases and Immunity in Global Health Program, McGill University Health Center and Research Institute, Montreal, Quebec, Canada., Petrof BJ; Meakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, Quebec, Canada.; Translational Research in Respiratory Diseases Program, McGill University Health Center and Research Institute, Montreal, Quebec, Canada. |
| Abstrakt: |
Patients with cystic fibrosis (CF) often suffer from skeletal muscle atrophy, most often attributed to physical inactivity and nutritional factors. CF is also characterized by abnormally elevated systemic inflammation. However, it is unknown whether the lack of a functional CF transmembrane conductance regulator (CFTR) gene predisposes to exaggerated inflammation-induced muscle proteolysis. CF mice ( CFTR -/- ) and their wild-type (WT = CFTR +/+ ) littermate controls were systemically injected with Pseudomonas -derived lipopolysaccharide (LPS). After 24 h, the diaphragm and limb muscles (fast-twitch tibialis anterior, and slow-twitch soleus) were assessed for induction of inflammatory cytokines (TNFα, IL1β, and IL6), oxidative stress, canonical muscle proteolysis pathways (Calpain, Ubiquitin-Proteasome, Autophagy), muscle fiber histology, and diaphragm contractile function. At baseline, CF and WT muscles did not differ with respect to indices of inflammation, proteolysis, or contractile function. After LPS exposure, there was significantly greater induction of all proteolysis pathways (calpain activity; ubiquitin-proteasome: MuRF1 and Atrogin1; autophagy: LC3B, Gabarapl-1, and BNIP3) in CF mice for the diaphragm and tibialis anterior, but not the soleus. Proteolysis pathway upregulation and correlations with inflammatory cytokine induction were most prominent in the tibialis anterior. Diaphragm force normalized to muscle cross-sectional area was reduced by LPS to an equivalent degree in CF and WT mice. CF skeletal muscles containing a high proportion of fast-twitch fibers (diaphragm, tibialis anterior) exhibit abnormally exaggerated upregulation of multiple muscle wasting pathways after exposure to an acute inflammatory stimulus, but not under basal conditions. |
