Corticortophin releasing factor 2 receptor agonist treatment significantly slows disease progression in mdx mice

<p>Abstract</p> <p>Background</p> <p>Duchenne muscular dystrophy results from mutation of the dystrophin gene, causing skeletal and cardiac muscle loss of function. The mdx mouse model of Duchenne muscular dystrophy is widely utilized to evaluate the potential of therapeutic regimens to modulate the loss of skeletal muscle function associated with dystrophin mutation. Importantly, progressive loss of diaphragm function is the most consistent striated muscle effect observed in the mdx mouse model, which is the same as in patients suffering from Duchenne muscular dystrophy.</p> <p>Methods</p> <p>Using the mdx mouse model, we have evaluated the effect that corticotrophin releasing factor 2 receptor (CRF2R) agonist treatment has on diaphragm function, morphology and gene expression.</p> <p>Results</p> <p>We have observed that treatment with the potent CRF2R-selective agonist PG-873637 prevents the progressive loss of diaphragm specific force observed during aging of mdx mice. In addition, the combination of PG-873637 with glucocorticoids not only prevents the loss of diaphragm specific force over time, but also results in recovery of specific force. Pathological analysis of CRF2R agonist-treated diaphragm muscle demonstrates that treatment reduces fibrosis, immune cell infiltration, and muscle architectural disruption. Gene expression analysis of CRF2R-treated diaphragm muscle showed multiple gene expression changes including globally decreased immune cell-related gene expression, decreased extracellular matrix gene expression, increased metabolism-related gene expression, and, surprisingly, modulation of circadian rhythm gene expression.</p> <p>Conclusion</p> <p>Together, these data demonstrate that CRF2R activation can prevent the progressive degeneration of diaphragm muscle associated with dystrophin gene mutation.</p

Activation of the dopamine 1 and dopamine 5 receptors increase skeletal muscle mass and force production under non-atrophying and atrophying conditions

<p>Abstract</p> <p>Background</p> <p>Control of skeletal muscle mass and force production is a complex physiological process involving numerous regulatory systems. Agents that increase skeletal muscle cAMP levels have been shown to modulate skeletal muscle mass and force production. The dopamine 1 receptor and its closely related homolog, the dopamine 5 receptor, are G-protein coupled receptors that are expressed in skeletal muscle and increase cAMP levels when activated. Thus we hypothesize that activation of the dopamine 1 and/or 5 receptor will increase skeletal muscle cAMP levels thereby modulating skeletal muscle mass and force production.</p> <p>Methods</p> <p>We treated isolated mouse tibialis anterior (TA) and medial gastrocnemius (MG) muscles in tissue bath with the selective dopamine 1 receptor and dopamine 5 receptor agonist SKF 81297 to determine if activation of skeletal muscle dopamine 1 and dopamine 5 receptors will increase cAMP. We dosed wild-type mice, dopamine 1 receptor knockout mice and dopamine 5 receptor knockout mice undergoing casting-induced disuse atrophy with SKF 81297 to determine if activation of the dopamine 1 and dopamine 5 receptors results in hypertrophy of non-atrophying skeletal muscle and preservation of atrophying skeletal muscle mass and force production.</p> <p>Results</p> <p>In tissue bath, isolated mouse TA and MG muscles responded to SKF 81297 treatment with increased cAMP levels. Treating wild-type mice with SKF 81297 reduced casting-induced TA and MG muscle mass loss in addition to increasing the mass of non-atrophying TA and MG muscles. In dopamine 1 receptor knockout mice, extensor digitorum longus (EDL) and soleus muscle mass and force was not preserved during casting with SKF 81297 treatment, in contrast to significant preservation of casted wild-type mouse EDL and soleus mass and EDL force with SKF 81297 treatment. Dosing dopamine 5 receptor knockout mice with SKF 81297 did not significantly preserve EDL and soleus muscle mass and force although wild-type mouse EDL mass and force was significantly preserved SKF 81297 treatment.</p> <p>Conclusions</p> <p>These data demonstrate for the first time that treatment with a dopamine 1/5 receptor agonist results in (1) significant preservation of EDL, TA, MG and soleus muscle mass and EDL muscle force production during periods of atrophy and (2) hypertrophy of TA and MG muscle. These effects appear to be mainly mediated by both the dopamine 1 and dopamine 5 receptors.</p

Treatment with a corticotrophin releasing factor 2 receptor agonist modulates skeletal muscle mass and force production in aged and chronically ill animals

<p>Abstract</p> <p>Background</p> <p>Muscle weakness is associated with a variety of chronic disorders such as emphysema (EMP) and congestive heart failure (CHF) as well as aging. Therapies to treat muscle weakness associated with chronic disease or aging are lacking. Corticotrophin releasing factor 2 receptor (CRF2R) agonists have been shown to maintain skeletal muscle mass and force production in a variety of acute conditions that lead to skeletal muscle wasting.</p> <p>Hypothesis</p> <p>We hypothesize that treating animals with a CRF2R agonist will maintain skeletal muscle mass and force production in animals with chronic disease and in aged animals.</p> <p>Methods</p> <p>We utilized animal models of aging, CHF and EMP to evaluate the potential of CRF2R agonist treatment to maintain skeletal muscle mass and force production in aged animals and animals with CHF and EMP.</p> <p>Results</p> <p>In aged rats, we demonstrate that treatment with a CRF2R agonist for up to 3 months results in greater extensor digitorum longus (EDL) force production, EDL mass, soleus mass and soleus force production compared to age matched untreated animals. In the hamster EMP model, we demonstrate that treatment with a CRF2R agonist for up to 5 months results in greater EDL force production in EMP hamsters when compared to vehicle treated EMP hamsters and greater EDL mass and force in normal hamsters when compared to vehicle treated normal hamsters. In the rat CHF model, we demonstrate that treatment with a CRF2R agonist for up to 3 months results in greater EDL and soleus muscle mass and force production in CHF rats and normal rats when compared to the corresponding vehicle treated animals.</p> <p>Conclusions</p> <p>These data demonstrate that the underlying physiological conditions associated with chronic diseases such as CHF and emphysema in addition to aging do not reduce the potential of CRF2R agonists to maintain skeletal muscle mass and force production.</p

Observation of a noise-induced transition with an analog simulator.

The first measurements are presented of the phase diagram of a noise-induced phase transition for a model, nonlinear system with multiplicative noise proposed by Horsthemke and Lefever. Measurements of two of the critical exponents are also presented. The present results are in good agreement with theoretical predictions based on the Stratonovic treatment of the stochastic evolution equation

Oscillating blue stragglers, gamma Doradus stars and eclipsing binaries in the open cluster NGC 2506

International audienceContext: This is the first step in a project to combine studies of eclipsing binaries and oscillating stars to probe the interior of Blue Stragglers (BS). This may imply a way to discriminate observationally between different birth mechanisms of BS stars. Aims: We study the open cluster NGC 2506 which contains oscillating BS stars and detached eclipsing binaries for which accurate parameters can be derived. This will tightly constrain the cluster isochrone and provide an absolute mass, radius and luminosity-scale for the cluster stars along with the cluster age, metallicity and distance. The present work focuses on obtaining the light curves of the binaries and determine their orbital periods, on obtaining power spectra of the oscillating BS stars to select targets for follow-up studies, and on searching for gamma Doradus type variables which are also expected to be present in the cluster. Methods: With a two-colour, dual-site photometric campaign we obtained 3120 CCD-images of NGC 2506 spread over four months. We analysed the BI time-series of the oscillating stars and used simulations to derive statistical uncertainties of the resulting frequencies, amplitudes and phases. A preliminary mode-identification was performed using frequency ratios for the oscillating BS stars, and amplitude ratios and phase differences for a population of newly detected gamma Doradus stars. Results: We quadrupled the number of known variables in NGC 2506 by discovering 3 new oscillating BS stars, 15 gamma Doradus stars and four new eclipsing binaries. The orbital periods of 2 known, detached eclipsing binaries were derived. We discovered a BS star with both p-mode and g-mode variability and we confronted our gamma Doradus observations with state-of-the-art seismic models, but found significant discrepancy between theory and observations. Conclusions: . NGC 2506 is an excellent target for asteroseismic tests of stellar models, as strong external constraints can be imposed on the models of a population of more than 20 oscillating stars of different types

Oscillating blue stragglers, gamma Doradus stars and eclipsing binaries in the open cluster NGC 2506

International audienceContext: This is the first step in a project to combine studies of eclipsing binaries and oscillating stars to probe the interior of Blue Stragglers (BS). This may imply a way to discriminate observationally between different birth mechanisms of BS stars. Aims: We study the open cluster NGC 2506 which contains oscillating BS stars and detached eclipsing binaries for which accurate parameters can be derived. This will tightly constrain the cluster isochrone and provide an absolute mass, radius and luminosity-scale for the cluster stars along with the cluster age, metallicity and distance. The present work focuses on obtaining the light curves of the binaries and determine their orbital periods, on obtaining power spectra of the oscillating BS stars to select targets for follow-up studies, and on searching for gamma Doradus type variables which are also expected to be present in the cluster. Methods: With a two-colour, dual-site photometric campaign we obtained 3120 CCD-images of NGC 2506 spread over four months. We analysed the BI time-series of the oscillating stars and used simulations to derive statistical uncertainties of the resulting frequencies, amplitudes and phases. A preliminary mode-identification was performed using frequency ratios for the oscillating BS stars, and amplitude ratios and phase differences for a population of newly detected gamma Doradus stars. Results: We quadrupled the number of known variables in NGC 2506 by discovering 3 new oscillating BS stars, 15 gamma Doradus stars and four new eclipsing binaries. The orbital periods of 2 known, detached eclipsing binaries were derived. We discovered a BS star with both p-mode and g-mode variability and we confronted our gamma Doradus observations with state-of-the-art seismic models, but found significant discrepancy between theory and observations. Conclusions: . NGC 2506 is an excellent target for asteroseismic tests of stellar models, as strong external constraints can be imposed on the models of a population of more than 20 oscillating stars of different types

Postponement of Hopf bifurcations by multiplicative colored noise.

Problems related to the definition of a Hopf bifurcation in the presence of noise are discussed in terms of three physical observables: the correlation functions, the power spectra, and the statistical densities. Of these, only the statistical density exhibits a distinct noise-induced transition. For a specific definition, only postponements are observed in analog simulator experiments with a Brusselator subject to white and colored noise on the control parameter. A recent prediction due to Lefever and Turner [Phys. Rev. Leu. 56, 1631 (1986)] is qualitatively tested