L-type Ca2+ channel contributes to alterations in mitochondrial calcium handling in the mdx ventricular myocyte

2013 ◽  
Vol 304 (6) ◽  
pp. H767-H775 ◽  
Author(s):  
Helena M. Viola ◽  
Stefan M. K. Davies ◽  
Aleksandra Filipovska ◽  
Livia C. Hool
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Mitochondrial Function ◽  
Ventricular Myocytes ◽  
Chain Complex ◽  
Cytoskeletal Proteins ◽  
Calcium Handling ◽  
Complex Activity ◽  
Whole Cell ◽  
Channel Current

The L-type Ca2+ channel is the main route for calcium entry into cardiac myocytes, and it is essential for contraction. Alterations in whole cell L-type Ca2+ channel current and Ca2+ homeostasis have been implicated in the development of cardiomyopathies. Cytoskeletal proteins can influence whole cell L-type Ca2+ current and mitochondrial function. Duchenne muscular dystrophy is a fatal X-linked disease that leads to progressive muscle weakness due to the absence of cytoskeletal protein dystrophin. This includes dilated cardiomyopathy, but the mechanisms are not well understood. We sought to identify the effect of alterations in whole cell L-type Ca2+ channel current on mitochondrial function in the murine model of Duchenne muscular dystrophy ( mdx). Activation of the L-type Ca2+ channel with the dihydropyridine agonist BayK(−) caused a significantly larger increase in cytosolic Ca2+ in mdx vs. wild-type ( wt) ventricular myocytes. Consistent with elevated cytosolic Ca2+, resting mitochondrial Ca2+, NADH, and mitochondrial superoxide were significantly greater in mdx vs. wt myocytes. Activation of the channel with BayK(−) caused a further increase in mitochondrial Ca2+, NADH, and superoxide in mdx myocytes. The ratios of the increases were similar to the ratios recorded in wt myocytes. In mitochondria isolated from 8-wk-old mdx hearts, respiration and mitochondrial electron transport chain complex activity were similar to mitochondria isolated from wt hearts. We conclude that mitochondria function at a higher level of resting calcium in the intact mdx myocyte and activation of the L-type Ca2+ channel contributes to alterations in calcium handling by the mitochondria. This perturbation may contribute to the development of cardiomyopathy.

Talin, vinculin and DRP (utrophin) concentrations are increased at mdx myotendinous junctions following onset of necrosis

1994 ◽  
Vol 107 (6) ◽  
pp. 1477-1483 ◽  
Author(s):  
D.J. Law ◽  
D.L. Allen ◽  
J.G. Tidball
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Cytoskeletal Proteins ◽  
Mdx Mouse ◽  
Mdx Mice ◽  
Myotendinous Junction ◽  
Glycoprotein Complex ◽  
Transmembrane Glycoprotein ◽  
Muscle Necrosis ◽  
Myotendinous Junctions

Duchenne muscular dystrophy (DMD) and the myopathy seen in the mdx mouse both result from absence of the protein dystrophin. Structural similarities between dystrophin and other cytoskeletal proteins, its enrichment at myotendinous junctions, and its indirect association with laminin mediated by a transmembrane glycoprotein complex suggest that one of dystrophin's functions in normal muscle is to form one of the links between the actin cytoskeleton and the extracellular matrix. Unlike Duchenne muscular dystrophy patients, mdx mice suffer only transient muscle necrosis, and are able to regenerate damaged muscle tissue. The present study tests the hypothesis that mdx mice partially compensate for dystrophin's absence by upregulating one or more dystrophin-independent mechanisms of cytoskeleton-membrane association. Quantitative analysis of immunoblots of adult mdx muscle samples showed an increase of approximately 200% for vinculin and talin, cytoskeletal proteins that mediate thin filament-membrane interactions at myotendinous junctions. Blots also showed an increase (143%) in the dystrophin-related protein called utrophin, another myotendinous junction constituent, which may be able to substitute for dystrophin directly. Muscle samples from 2-week-old animals, a period immediately preceding the onset of muscle necrosis, showed no significant differences in protein concentration between mdx and controls. Quantitative analyses of confocal images of myotendinous junctions from mdx and control muscles show significantly higher concentrations of talin and vinculin at the myotendinous junctions of mdx muscle. These findings indicate that mdx mice may compensate in part for the absence of dystrophin by increased expression of other molecules that subsume dystrophin's mechanical function.

Dietary dimethylglycine sodium salt supplementation improves growth performance, redox status, and skeletal muscle function of intrauterine growth restriction weaned piglets

2021 ◽  
Author(s):  
Kaiwen Bai ◽  
Luyi Jiang ◽  
Qiming Li ◽  
Jingfei Zhang ◽  
Lili Zhang ◽  
...  
Keyword(s):  
Growth Performance ◽  
Mitochondrial Function ◽  
Chain Complex ◽  
Basal Diet ◽  
Mitochondrial Respiratory Chain ◽  
Redox Status ◽  
Weaned Piglets ◽  
Complex Activity ◽  
Mitochondrial Respiratory Chain Complex ◽  
Intrauterine Growth

Abstract Few studies have focused on the role of dimethylglycine sodium salt (DMG-Na) in protecting the redox status of skeletal muscle, although it is reported to be beneficial in animal husbandry. This study investigated the beneficial effects of DMG-Na on the growth performance, longissimus dorsi muscle (LM) redox status, and mitochondrial function in weaning piglets that were intrauterine growth restricted (IUGR). Ten normal birth weight (NBW) newborn piglets (1.53 ± 0.04 kg) and 20 IUGR newborn piglets (0.76 ± 0.06 kg) from ten sows were obtained. All piglets were weaned at 21 days of age and allocated to three groups with ten replicates per group: NBW-weaned piglets fed a common basal diet (N); IUGR weaned piglets fed a common basal diet (I); IUGR weaned piglets fed a common basal diet supplemented with 0.1% DMG-Na (ID). They were slaughtered at 49 days of age to collect the serum and LM samples. Compared with the N group, the growth performance, LM structure, serum, and, within the LM, mitochondrial redox status, mitochondrial respiratory chain complex activity, energy metabolites, redox status-related, cell adhesion-related, and mitochondrial function-related gene expression, and protein expression deteriorated in group I (P < 0.05). The ID group showed improved growth performance, LM structure, serum, and, within the LM, mitochondrial redox status, mitochondrial respiratory chain complex activity, energy metabolites, redox status-related, cell adhesion-related, and mitochondrial function-related gene expression, and protein expression compared with those in the I group (P < 0.05). The above results indicated that the DMG-Na treatment could improve the LM redox status and mitochondrial function in IUGR weaned piglets via the Nuclear factor erythroid 2-related factor 2 (Nrf2)/ Sirtuin 1 (SIRT1)/ Peroxisome proliferator-activated receptorγcoactivator-1α (PGC1α) network, thus improving their growth performance.

scholarly journals Selective PPARδ Modulators Improve Mitochondrial Function: Potential Treatment for Duchenne Muscular Dystrophy (DMD)

2018 ◽  
Vol 9 (9) ◽  
pp. 935-940 ◽  
Author(s):  
Bharat Lagu ◽  
Arthur F. Kluge ◽  
Effie Tozzo ◽  
Ross Fredenburg ◽  
Eric L. Bell ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Mitochondrial Function ◽  
Potential Treatment ◽  
Function Potential

scholarly journals Function and Genetics of Dystrophin and Dystrophin-Related Proteins in Muscle

2002 ◽  
Vol 82 (2) ◽  
pp. 291-329 ◽  
Author(s):  
Derek J. Blake ◽  
Andrew Weir ◽  
Sarah E. Newey ◽  
Kay E. Davies
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Protein Complex ◽  
Muscle Disease ◽  
Calcium Handling ◽  
Dystrophic Muscle ◽  
Gene Encoding ◽  
Muscle Wasting Disease ◽  
Novel Therapeutic Strategies ◽  
Related Proteins

The X-linked muscle-wasting disease Duchenne muscular dystrophy is caused by mutations in the gene encoding dystrophin. There is currently no effective treatment for the disease; however, the complex molecular pathology of this disorder is now being unravelled. Dystrophin is located at the muscle sarcolemma in a membrane-spanning protein complex that connects the cytoskeleton to the basal lamina. Mutations in many components of the dystrophin protein complex cause other forms of autosomally inherited muscular dystrophy, indicating the importance of this complex in normal muscle function. Although the precise function of dystrophin is unknown, the lack of protein causes membrane destabilization and the activation of multiple pathophysiological processes, many of which converge on alterations in intracellular calcium handling. Dystrophin is also the prototype of a family of dystrophin-related proteins, many of which are found in muscle. This family includes utrophin and α-dystrobrevin, which are involved in the maintenance of the neuromuscular junction architecture and in muscle homeostasis. New insights into the pathophysiology of dystrophic muscle, the identification of compensating proteins, and the discovery of new binding partners are paving the way for novel therapeutic strategies to treat this fatal muscle disease. This review discusses the role of the dystrophin complex and protein family in muscle and describes the physiological processes that are affected in Duchenne muscular dystrophy.

scholarly journals β-Glucans as Dietary Supplement to Improve Locomotion and Mitochondrial Respiration in a Model of Duchenne Muscular Dystrophy

Nutrients ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1619
Author(s):  
Letizia Brogi ◽  
Maria Marchese ◽  
Alessandro Cellerino ◽  
Rosario Licitra ◽  
Valentina Naef ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Immune Responses ◽  
Mitochondrial Function ◽  
Mitochondrial Respiration ◽  
Life Quality ◽  
Adaptive Immune ◽  
Progressive Muscle Weakness ◽  
Diet Supplement ◽  
And Oxidative Stress

Duchenne muscular dystrophy (DMD) is a severe X-linked neuromuscular childhood disorder that causes progressive muscle weakness and degeneration. A lack of dystrophin in DMD leads to inflammatory response, autophagic dysregulation, and oxidative stress in skeletal muscle fibers that play a key role in the progression of the pathology. β-glucans can modulate immune function by modifying the phagocytic activity of immunocompetent cells, notably macrophages. Mitochondrial function is also involved in an important mechanism of the innate and adaptive immune responses, owing to high need for energy of immune cells. In the present study, the effects of 1,3-1,6 β-glucans on five-day-old non-dystrophic and dystrophic (sapje) zebrafish larvae were investigated. The effects of the sonication of β-glucans and the dechorionation of embryos were also evaluated. The results showed that the incidence of dystrophic phenotypes was reduced when dystrophic embryos were exposed to 2 and 4 mg L−1 of 1,3-1,6 β-glucans. Moreover, when the dystrophic larvae underwent 8 mg L−1 treatment, an improvement of the locomotor performances and mitochondrial respiration were observed. In conclusion, the observed results demonstrated that 1,3-1,6 β-glucans improve locomotor performances and mitochondrial function in dystrophic zebrafish. Therefore, for ameliorating their life quality, 1,3-1,6 β-glucans look like a promising diet supplement for DMD patients, even though further investigations are required.

scholarly journals Dysregulation of Calcium Handling in Duchenne Muscular Dystrophy-Associated Dilated Cardiomyopathy: Mechanisms and Experimental Therapeutic Strategies

2020 ◽  
Vol 9 (2) ◽  
pp. 520 ◽  
Author(s):  
Michelle L. Law ◽  
Houda Cohen ◽  
Ashley A. Martin ◽  
Addeli Bez Batti Angulski ◽  
Joseph M. Metzger
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Dilated Cardiomyopathy ◽  
Cardiac Myocyte ◽  
Contractile Function ◽  
Cytosolic Calcium ◽  
Therapeutic Strategies ◽  
Calcium Handling ◽  
Cardiac Contractile Function ◽  
Mechanistic Basis

Duchenne muscular dystrophy (DMD) is an X-linked recessive disease resulting in the loss of dystrophin, a key cytoskeletal protein in the dystrophin-glycoprotein complex. Dystrophin connects the extracellular matrix with the cytoskeleton and stabilizes the sarcolemma. Cardiomyopathy is prominent in adolescents and young adults with DMD, manifesting as dilated cardiomyopathy (DCM) in the later stages of disease. Sarcolemmal instability, leading to calcium mishandling and overload in the cardiac myocyte, is a key mechanistic contributor to muscle cell death, fibrosis, and diminished cardiac contractile function in DMD patients. Current therapies for DMD cardiomyopathy can slow disease progression, but they do not directly target aberrant calcium handling and calcium overload. Experimental therapeutic targets that address calcium mishandling and overload include membrane stabilization, inhibition of stretch-activated channels, ryanodine receptor stabilization, and augmentation of calcium cycling via modulation of the Serca2a/phospholamban (PLN) complex or cytosolic calcium buffering. This paper addresses what is known about the mechanistic basis of calcium mishandling in DCM, with a focus on DMD cardiomyopathy. Additionally, we discuss currently utilized therapies for DMD cardiomyopathy, and review experimental therapeutic strategies targeting the calcium handling defects in DCM and DMD cardiomyopathy.

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