Ons on the tracheal smooth muscle membrane are markedly lowered in tissue from mdx mice.Moreover, there is a redistribution of caveolae-like structures, as they appear to become internalized in absence of dystrophin. We agree that there is a limitation of this analysis, as we didn’t execute immunogold staining for caveolin-1. However, our prior work has shown powerful correlation amongst the internalization of membrane caveolae with all the decreased expression of contractile protein markers and key-signaling molecules (PLCb1 and Gaq) needed for receptor-mediated Ca2+ release [46,47]. We have also showed that trafficking of caveolin-1 protein together with DGC subunits from caveolae-rich fractions to non-caveolae fraction is affected when tethering of actin to dystrophin was perturbed [46]. A great deal of what is known about dystrophin structurefunction has come from studies of various dystrophin-deficient animals [17,23], but by far probably the most prolific model has been the mdx mouse, 1st described in 1984 by Bulfield et al [16]. The skeletal muscle tissues of mdx mice show a marked susceptibility to lengthening contraction-mediated force decrements [847].Datopotamab deruxtecan Contractile dysfunctions are also evident in cardiac muscle tissues of the mdx mouse [88,89].Aldosterone These observations recommend that dystrophin is significant in excitation-contraction coupling of skeletal and cardiac muscles and lead us to investigate its role in lung physiology.PMID:27017949 Our benefits with mdx mice are suggestive with the fact that dystrophin may well have an effect on airway and lung function. We observed a statistically important reduction in airway resistance in mdx mice in the highest concentration of aerosolized MCh, even though at reduced MCh concentrations these values failed to achieve statistical significance. Notably for our work we applied 8-week old young adult mice. The nature of our findings and information that the dystrophic muscle phenotype is progressive in nature [202] recommend a need to have for future studies in which lung function is followed as mice age past eight weeks. In summary, our study investigated the role of dystrophin in phenotype maturation of ASM cells and the association of dystrophin deficiency with activity of signaling proteins essential for improvement of a contractile phenotype in vitro. Ex vivo tracheal smooth muscle contraction data making use of mdx mice clearly show that dystrophin is necessary for creating contractile force in response to muscarinic agonist. These findings did not translate fully towards the intact animal exactly where we identified no significant decline of lung function in the mdx mice at reduced concentrations of MCh, although we did observe a important reduction in the airway resistance at the highest concentrations of MCh. Collectively, our information suggests that additional studies are warranted to assess the influence of aging on airway physiology in dystrophin deficient models as the final results presented within the current study have been done on young mdx mice.AcknowledgmentsWe would like to thank Dr. M K Childers (Wake Forest University, Winston, NC, USA) for kindly supplying us with canine tissues.Author ContributionsConceived and created the experiments: PS AJH. Performed the experiments: PS SB RWM GS. Analyzed the data: PS AJH. Contributed reagents/materials/analysis tools: JEA. Wrote the paper: PS.
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