scholarly journals Deficit in PINK1/PARKIN-mediated mitochondrial autophagy at late stages of dystrophic cardiomyopathy

2017 ◽  
Vol 114 (1) ◽  
pp. 90-102 ◽  
Author(s):  
Chifei Kang ◽  
Myriam A Badr ◽  
Viktoriia Kyrychenko ◽  
Eeva-Liisa Eskelinen ◽  
Natalia Shirokova
Keyword(s):  
Structural Damage ◽  
Imaging Techniques ◽  
Structure And Function ◽  
Muscle Disease ◽  
Cardiac Complications ◽  
Mdx Mice ◽  
Defective Structure ◽  
Atp Production ◽  
Dystrophic Cardiomyopathy ◽  
And Function

Abstract Aims Duchenne muscular dystrophy (DMD) is an inherited devastating muscle disease with severe and often lethal cardiac complications. Emerging evidence suggests that the evolution of the pathology in DMD is accompanied by the accumulation of mitochondria with defective structure and function. Here, we investigate whether defects in the housekeeping autophagic pathway contribute to mitochondrial and metabolic dysfunctions in dystrophic cardiomyopathy. Methods and results We employed various biochemical and imaging techniques to assess mitochondrial structure and function as well as to evaluate autophagy, and specific mitochondrial autophagy (mitophagy), in hearts of mdx mice, an animal model of DMD. Our results indicate substantial structural damage of mitochondria and a significant decrease in ATP production in hearts of mdx animals, which developed cardiomyopathy. In these hearts, we also detected enhanced autophagy but paradoxically, mitophagy appeared to be suppressed. In addition, we found decreased levels of several proteins involved in the PINK1/PARKIN mitophagy pathway as well as an insignificant amount of PARKIN protein phosphorylation at the S65 residue upon induction of mitophagy. Conclusions Our results suggest faulty mitophagy in dystrophic hearts due to defects in the PINK1/PARKIN pathway.

Normal ageing and the brain

1998 ◽  
Vol 15 (1) ◽  
pp. 26-28
Author(s):  
CS Breathnach
Keyword(s):  
Cerebral Cortex ◽  
Imaging Techniques ◽  
Structure And Function ◽  
Ageing Population ◽  
Cell Shrinkage ◽  
Ageing Processes ◽  
Normal Ageing ◽  
And Function ◽  
Ageing Brain ◽  
The Brain

AbstractInterest in the psychiatric aspects of old age predated the institution of geriatrics as a clinical discipline, but the systematic study of the ageing brain only began in the second half of this century when an ageing population presented a global numerical challenge to society. In the senescent cerebral cortex, though the number of neurons is not reduced, cell shrinkage results in synaptic impoverishment with consequent cognitive impairment. Recent advances in imaging techniques, combined with burgeoning knowledge of neurobiological structure and function, have increased our understanding of the ageing processes in the human brain and permit an optimistic approach in the application of the newer insights into neuropsychology and geriatric psychiatry.

Respiratory muscle imaging by ultrasound and MRI in neuromuscular disorders

2021 ◽  
pp. 2100137
Author(s):  
Jeroen L.M. van Doorn ◽  
Francesca Pennati ◽  
Hendrik H.G. Hansen ◽  
Baziel G.M. van Engelen ◽  
Andrea Aliverti ◽  
...  
Keyword(s):  
Respiratory Muscle ◽  
Imaging Techniques ◽  
Neuromuscular Disorders ◽  
Respiratory Muscles ◽  
Daily Practice ◽  
Structure And Function ◽  
Muscle Structure ◽  
Respiratory Management ◽  
Technological Developments ◽  
And Function

Respiratory muscle weakness is common in neuromuscular disorders and leads to significant respiratory difficulties. Therefore, reliable and easy assessment of respiratory muscle structure and function in neuromuscular disorders is crucial. In the last decade, ultrasound and MRI emerged as promising imaging techniques to assess respiratory muscle structure and function. Respiratory muscle imaging directly measures the respiratory muscles and, in contrast to pulmonary function testing, is independent of patient effort. This makes respiratory muscle imaging suitable to use as tool in clinical respiratory management and as outcome parameter in upcoming drug trials for neuromuscular disorders, particularly in children. In this narrative review, we discuss the latest studies and technological developments in imaging of the respiratory muscles by US and MR, and its clinical application and limitations. We aim to increase understanding of respiratory muscle imaging and facilitate its use as outcome measure in daily practice and clinical trials.

scholarly journals Renal ischemia alters expression of mitochondria-related genes and impairs mitochondrial structure and function in swine scattered tubular-like cells

2020 ◽  
Vol 319 (1) ◽  
pp. F19-F28 ◽  
Author(s):  
Rahele A. Farahani ◽  
Xiang-Yang Zhu ◽  
Hui Tang ◽  
Kyra L. Jordan ◽  
Lilach O. Lerman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Structural Damage ◽  
Nuclear Dna ◽  
Mitochondrial Genes ◽  
Structure And Function ◽  
Mitochondrial Damage ◽  
Renal Ischemia ◽  
Gene Gain ◽  
Mitochondrial Structure ◽  
And Function

Scattered tubular-like cells (STCs) are dedifferentiated surviving tubular epithelial cells that repair neighboring injured cells. Experimental renal artery stenosis (RAS) impairs STC reparative potency by inducing mitochondrial injury, but the exact mechanisms of mitochondrial damage remain unknown. We hypothesized that RAS alters expression of mitochondria-related genes, contributing to mitochondrial structural damage and dysfunction in swine STCs. CD24+/CD133+ STCs were isolated from pig kidneys after 10 wk of RAS or sham ( n = 3 each). mRNA sequencing was performed, and nuclear DNA (nDNA)-encoded mitochondrial genes and mitochondrial DNA (mtDNA)-encoded genes were identified. Mitochondrial structure, ATP generation, biogenesis, and expression of mitochondria-associated microRNAs were also assessed. There were 96 nDNA-encoded mitochondrial genes upregulated and 12 mtDNA-encoded genes downregulated in RAS-STCs versus normal STCs. Functional analysis revealed that nDNA-encoded and mtDNA-encoded differentially expressed genes were primarily implicated in mitochondrial respiration and ATP synthesis. Mitochondria from RAS STCs were swollen and showed cristae remodeling and loss and decreased ATP production. Immunoreactivity of the mitochondrial biogenesis marker peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α and expression of the mitochondria-associated microRNAs miR-15a, miR-181a, miR-196a, and miR-296-3p, which target several mtDNA genes, were higher in RAS-STCs compared with normal STCs, suggesting a potential modulation of mitochondria-related gene expression. These results demonstrate that RAS induces an imbalance in mtDNA- and nDNA-mitochondrial gene expression, impairing mitochondrial structure and function in swine STCs. These observations support development of gene gain- and loss-of-function strategies to ameliorate mitochondrial damage and preserve the reparative potency of STCs in patients with renal ischemia.

scholarly journals Novel model of distal myopathy caused by the myosin rod mutation R1500P disrupts acto-myosin binding

2019 ◽  
Author(s):  
Genevieve C. K. Wilson ◽  
Ada Buvoli ◽  
Massimo Buvoli ◽  
Kathleen C. Woulfe ◽  
Lori A. Walker ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Structure And Function ◽  
Muscle Disease ◽  
Therapeutic Interventions ◽  
Small Subset ◽  
Histological Structure ◽  
Distal Myopathy ◽  
Myosin Binding ◽  
And Function ◽  
Myosin Rod

AbstractIntroductionMore than 400 mutations in β-myosin, a slow myosin motor, can cause both cardiac and skeletal myopathy in humans. A small subset of these mutations, mostly located in the myosin rod, leads to a progressive skeletal muscle disease known as Laing distal myopathy (MPD1). While this disease has previously been studied using a variety of systems, it has never been studied in the mammalian muscle environment. Here, we describe a mouse model for the MPD1-causing mutation R1500P to elucidate disease pathogenesis and to act as a future platform for testing therapeutic interventions.MethodsBecause mice have very few slow skeletal muscles compared to humans, we generated mice expressing the β-myosin R1500P mutation or WT β-myosin in fast skeletal muscle fibers and determined the structural and functional consequences of the R1500P mutation.ResultsThe mutant R1500P myosin affects both muscle histological structure and function and the mice exhibit a number of the histological hallmarks that are often identified in patients with MPD1. Furthermore, R1500P mice show decreased muscle strength and endurance, as well as ultrastructural abnormalities in the SR & t-tubules. Somewhat surprisingly because of its location in the rod, the R1500P mutation weakens acto-myosin binding by affecting cross-bridge detachment rate.ConclusionsWhile each group of MPD1-causing mutations most likely operates through distinct mechanisms, our model provides new insight into how a mutation in the rod domain impacts muscle structure and function and leads to disease.

scholarly journals Differential Effect of Calsequestrin Ablation on Structure and Function of Fast and Slow Skeletal Muscle Fibers

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Cecilia Paolini ◽  
Marco Quarta ◽  
Laura D'Onofrio ◽  
Carlo Reggiani ◽  
Feliciano Protasi
Keyword(s):  
Skeletal Muscle ◽  
Differential Effect ◽  
Structural Damage ◽  
Binding Proteins ◽  
Structure And Function ◽  
Tetanic Stimulation ◽  
Active Tension ◽  
Slow Skeletal Muscle ◽  
Time Parameters ◽  
And Function

We compared structure and function of EDL and Soleus muscles in adult (4–6 m) mice lacking both Calsequestrin (CASQ) isoforms, the main SR Ca2+-binding proteins. Lack of CASQ induced ultrastructural alterations in ~30% of Soleus fibers, but not in EDL. Twitch time parameters were prolonged in both muscles, although tension was not reduced. However, when stimulated for 2 sec at 100 hz, Soleus was able to sustain contraction, while in EDL active tension declined by 70–80%. The results presented in this paper unmask a differential effect of CASQ1&2 ablation in fast versus slow fibers. CASQ is essential in EDL to provide large amount of Ca2+released from the SR during tetanic stimulation. In contrast, Soleus deals much better with lack of CASQ because slow fibers require lower Ca2+amounts and slower cycling to function properly. Nevertheless, Soleus suffers more severe structural damage, possibly because SR Ca2+leak is more pronounced.

scholarly journals Systemic Microdystrophin Gene Delivery Improves Skeletal Muscle Structure and Function in Old Dystrophic mdx Mice

2008 ◽  
Vol 16 (4) ◽  
pp. 657-664 ◽  
Author(s):  
Paul Gregorevic ◽  
Michael J Blankinship ◽  
James M Allen ◽  
Jeffrey S Chamberlain
Keyword(s):  
Skeletal Muscle ◽  
Gene Delivery ◽  
Structure And Function ◽  
Mdx Mice ◽  
Muscle Structure ◽  
And Function

Alteration of structure and function of ATP synthase and cytochrome c oxidase by lack of Fo-a and Cox3 subunits caused by mitochondrial DNA 9205delTA mutation

2015 ◽  
Vol 466 (3) ◽  
pp. 601-611 ◽  
Author(s):  
Kateřina Hejzlarová ◽  
Vilma Kaplanová ◽  
Hana Nůsková ◽  
Nikola Kovářová ◽  
Pavel Ješina ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Cytochrome C Oxidase ◽  
Atp Synthase ◽  
Stop Codon ◽  
Threshold Effect ◽  
Structure And Function ◽  
Missense Mutations ◽  
Atp Production ◽  
Atp6 Gene ◽  
And Function

Mutations in the MT-ATP6 gene are frequent causes of severe mitochondrial disorders. Typically, these are missense mutations, but another type is represented by the 9205delTA microdeletion, which removes the stop codon of the MT-ATP6 gene and affects the cleavage site in the MT-ATP8/MT-ATP6/MT-CO3 polycistronic transcript. This interferes with the processing of mRNAs for the Atp6 (Fo-a) subunit of ATP synthase and the Cox3 subunit of cytochrome c oxidase (COX). Two cases described so far presented with strikingly different clinical phenotypes–mild transient lactic acidosis or fatal encephalopathy. To gain more insight into the pathogenic mechanism, we prepared 9205delTA cybrids with mutation load ranging between 52 and 99% and investigated changes in the structure and function of ATP synthase and the COX. We found that 9205delTA mutation strongly reduces the levels of both Fo-a and Cox3 proteins. Lack of Fo-a alters the structure but not the content of ATP synthase, which assembles into a labile, ∼60 kDa smaller, complex retaining ATP hydrolytic activity but which is unable to synthesize ATP. In contrast, lack of Cox3 limits the biosynthesis of COX but does not alter the structure of the enzyme. Consequently, the diminished mitochondrial content of COX and non-functional ATP synthase prevent most mitochondrial ATP production. The biochemical effects caused by the 9205delTA microdeletion displayed a pronounced threshold effect above ∼90% mutation heteroplasmy. We observed a linear relationship between the decrease in subunit Fo-a or Cox3 content and the functional presentation of the defect. Therefore we conclude that the threshold effect originated from a gene–protein level.

scholarly journals Net Zero and Catalysis: How Neutrons Can Help

Physchem ◽  
2021 ◽  
Vol 1 (1) ◽  
pp. 95-120
Author(s):  
Stewart F. Parker ◽  
David Lennon
Keyword(s):  
Imaging Techniques ◽  
Structure And Function ◽  
Methane Reforming ◽  
Fischer Tropsch ◽  
Catalyst Structure ◽  
Methanol Production ◽  
Net Zero ◽  
Widespread Acceptance ◽  
And Function ◽  
Insight Into

Net Zero has the aim of achieving equality between the amount of greenhouse gas emissions produced and the amount removed from the atmosphere. There is widespread acceptance that for Net Zero to be achievable, chemistry, and hence catalysis, must play a major role. Most current studies of catalysts and catalysis employ a combination of physical methods, imaging techniques and spectroscopy to provide insight into the catalyst structure and function. One of the methods used is neutron scattering and this is the focus of this Perspective. Here, we show how neutron methods are being used to study reactions and processes that are directly relevant to achieving Net Zero, such as methane reforming, Fischer–Tropsch synthesis, ammonia and methanol production and utilization, bio-mass upgrading, fuel cells and CO2 capture and exploitation. We conclude by describing some other areas that offer opportunities.

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