Cardiac phenotype of Duchenne Muscular Dystrophy: Insights from cellular studies

Dilated cardiomyopathy is a serious and almost inevitable complication of Duchenne Muscular Dystrophy, a devastating and fatal disease of skeletal muscle resulting from the lack of functional dystrophin, a protein linking the cytoskeleton to the extracellular matrix. Ultimately, it leads to congestive heart failure and arrhythmias resulting from both cardiac muscle fibrosis and impaired function of the remaining cardiomyocytes. Here we summarize findings obtained in several laboratories, focusing on cellular mechanisms that result in degradation of cardiac functions in dystrophy. This article is part of a Special Issue entitled "Calcium Signaling in Heart"

Dystrophic cardiomyopathy: amplification of cellular damage by Ca2+ signalling and reactive oxygen species-generating pathways

Aims Cardiac myopathies are the second leading cause of death in patients with Duchenne and Becker muscular dystrophy, the two most common and severe forms of a disabling striated muscle disease. Although the genetic defect has been identified as mutations of the dystrophin gene, very little is known about the molecular and cellular events leading to progressive cardiac muscle damage. Dystrophin is a protein linking the cytoskeleton to a complex of transmembrane proteins that interact with the extracellular matrix. The fragility of the cell membrane resulting from the lack of dystrophin is thought to cause an excessive susceptibility to mechanical stress. Here, we examined cellular mechanisms linking the initial membrane damage to the dysfunction of dystrophic heart. Methods and results Cardiac ventricular myocytes were enzymatically isolated from 5- to 9-month-old dystrophic mdx and wild-type (WT) mice. Cells were exposed to mechanical stress, applied as osmotic shock. Stress-induced cytosolic and mitochondrial Ca2+ signals, production of reactive oxygen species (ROS), and mitochondrial membrane potential were monitored with confocal microscopy and fluorescent indicators. Pharmacological tools were used to scavenge ROS and to identify their possible sources. Osmotic shock triggered excessive cytosolic Ca2+ signals, often lasting for several minutes, in 82% of mdx cells. In contrast, only 47% of the WT cardiomyocytes responded with transient and moderate intracellular Ca2+ signals. On average, the reaction was 6-fold larger in mdx cells. Removal of extracellular Ca2+ abolished these responses, implicating Ca2+ influx as a trigger for abnormal Ca2+ signalling. Our further experiments revealed that osmotic stress in mdx cells produced an increase in ROS production and mitochondrial Ca2+ overload. The latter was followed by collapse of the mitochondrial membrane potential, an early sign of cell death. Conclusion Overall, our findings reveal that excessive intracellular Ca2+ signals and ROS generation link the initial sarcolemmal injury to mitochondrial dysfunctions. The latter possibly contribute to the loss of functional cardiac myocytes and heart failure in dystrophy. Understanding the sequence of events of dystrophic cell damage and the deleterious amplification systems involved, including several positive feed-back loops, may allow for a rational development of novel therapeutic strategie

First Stages of Wet Wooden Ice-House Conservation Dated to the First Half of the 18th Century

In July 2019, during the restoration of the building of the First Cadet Corps (the former mansion of Aleksandr D. Menshikov), fragments of two structures that differ in the degree of preservation – a cellar and an ice-house (lednik), dating back to the first half of the 18th century, were discovered. The lednik is a traditional building for the North-Western region of Russia and a rare wooden architectural object for St. Petersburg of that time. In order to prepare the construction for dismantling and to plan its further restoration, preliminary studies were conducted. It was found that details from other wooden objects, probably ships and barges, were used for this construction. The physical parameters of the wood of the structural parts varied. Most parts of the lednik are waterlogged. Based on the results of the research, a plan was worked out for the preservation of this unique historical architectural object

Hierarchical accumulation of RyR post-translational modifications drives disease progression in dystrophic cardiomyopathy

Aims Duchenne muscular dystrophy (DMD) is a muscle disease with serious cardiac complications. Changes in Ca2+ homeostasis and oxidative stress were recently associated with cardiac deterioration, but the cellular pathophysiological mechanisms remain elusive. We investigated whether the activity of ryanodine receptor (RyR) Ca2+ release channels is affected, whether changes in function are cause or consequence and which post-translational modifications drive disease progression. Methods and results Electrophysiological, imaging, and biochemical techniques were used to study RyRs in cardiomyocytes from mdx mice, an animal model of DMD. Young mdx mice show no changes in cardiac performance, but do so after ∼8 months. Nevertheless, myocytes from mdx pups exhibited exaggerated Ca2+ responses to mechanical stress and ‘hypersensitive' excitation-contraction coupling, hallmarks of increased RyR Ca2+ sensitivity. Both were normalized by antioxidants, inhibitors of NAD(P)H oxidase and CaMKII, but not by NO synthases and PKA antagonists. Sarcoplasmic reticulum Ca2+ load and leak were unchanged in young mdx mice. However, by the age of 4-5 months and in senescence, leak was increased and load was reduced, indicating disease progression. By this age, all pharmacological interventions listed above normalized Ca2+ signals and corrected changes in ECC, Ca2+ load, and leak. Conclusion Our findings suggest that increased RyR Ca2+ sensitivity precedes and presumably drives the progression of dystrophic cardiomyopathy, with oxidative stress initiating its development. RyR oxidation followed by phosphorylation, first by CaMKII and later by PKA, synergistically contributes to cardiac deterioratio

The Discourse Personality of Politician Sergey Mikheyev with Regards to his Speech Behaviour

This paper presents the results of research into the linguistic personality of politician Sergey Mikheyev when viewed as a discourse personality. Special consideration has been given to the speech behaviour characteristic of a discourse personality. The paper presents the results of the cognitive-discursive and linguo-rhetorical description of a discourse personality.The relevance of this research is based on the growing interest for linguistic personality typology with regards to discourse (K. F. Sedov, V. I. Karasik, N. D. Golev, A. V. Bolotnov, et al.). A mixed type of political discourse that actualises both the personal and status factors of its formation was chosen as the object of analysis. The research focuses on semantic dominants and semantic constructs of the discourse behaviour of the Russian politician Sergey Mikheyev, as well as on the cognitive and linguo-rhetorical mechanisms of the interpretation of speech acts when viewed as elements of individual discourse behaviour. We define the linguo-rhetorical competence of the politician’s personality. The study is novel in that it identifies semantic dominants and semantic constructs found in Mikheyev’s discourse and uses an integrative approach to analysis (cognitive-discursive and linguo-rhetorical). It is proven that semantic dominants, constructs, and presuppositions manifest inventive mechanisms of individual discourse activity. We suggest defining the status of Mikheyev’s discourse personality as a mixed type of elitist linguistic personality that is pragmatically oriented. We prove that the discourse personality of Sergey Mikheyev is a prototype of a future successful politician’s linguistic personality. The paper presents the author’s original communicative competence system of S. Mikheyev’s discourse personality

Dystrophic cardiomyopathy: amplification of cellular damage by Ca2+ signalling and reactive oxygen species-generating pathways

AIMS: Cardiac myopathies are the second leading cause of death in patients with Duchenne and Becker muscular dystrophy, the two most common and severe forms of a disabling striated muscle disease. Although the genetic defect has been identified as mutations of the dystrophin gene, very little is known about the molecular and cellular events leading to progressive cardiac muscle damage. Dystrophin is a protein linking the cytoskeleton to a complex of transmembrane proteins that interact with the extracellular matrix. The fragility of the cell membrane resulting from the lack of dystrophin is thought to cause an excessive susceptibility to mechanical stress. Here, we examined cellular mechanisms linking the initial membrane damage to the dysfunction of dystrophic heart. METHODS AND RESULTS: Cardiac ventricular myocytes were enzymatically isolated from 5- to 9-month-old dystrophic mdx and wild-type (WT) mice. Cells were exposed to mechanical stress, applied as osmotic shock. Stress-induced cytosolic and mitochondrial Ca(2+) signals, production of reactive oxygen species (ROS), and mitochondrial membrane potential were monitored with confocal microscopy and fluorescent indicators. Pharmacological tools were used to scavenge ROS and to identify their possible sources. Osmotic shock triggered excessive cytosolic Ca(2+) signals, often lasting for several minutes, in 82% of mdx cells. In contrast, only 47% of the WT cardiomyocytes responded with transient and moderate intracellular Ca(2+) signals. On average, the reaction was 6-fold larger in mdx cells. Removal of extracellular Ca(2+) abolished these responses, implicating Ca(2+) influx as a trigger for abnormal Ca(2+) signalling. Our further experiments revealed that osmotic stress in mdx cells produced an increase in ROS production and mitochondrial Ca(2+) overload. The latter was followed by collapse of the mitochondrial membrane potential, an early sign of cell death. CONCLUSION: Overall, our findings reveal that excessive intracellular Ca(2+) signals and ROS generation link the initial sarcolemmal injury to mitochondrial dysfunctions. The latter possibly contribute to the loss of functional cardiac myocytes and heart failure in dystrophy. Understanding the sequence of events of dystrophic cell damage and the deleterious amplification systems involved, including several positive feed-back loops, may allow for a rational development of novel therapeutic strategies