53 research outputs found
Cellular and molecular anatomy of the mammalian neuromuscular junction in health and disease
The vast diversity across the animal kingdom and in particular within the
class of mammals is not only of evolutionary interest, but also plays an
important role in framing the context of research in which mammalian animal
models are utilised. Research addressing neurodegenerative diseases has
struggled to translate from the widely used mouse model to humans. We now
know the neuromuscular junction (NMJ) - the key player responsible for
generation of movement and often a target in disease - is strikingly different
between mouse and human, thus questioning the validity of rodent models.
Building upon recent studies assessing the healthy human NMJ, this project
directly sought to examine the human NMJ in disease and whether
predictions made from mouse models also applied in humans. Furthermore,
this project aimed to identify mammalian models more similar to human NMJ
morphology, which could be used as alternatives to the mouse. Following
morphological NMJ analysis of the human and mammalian NMJ, molecular
pathways contributing to the stability of the human NMJ during healthy
ageing of muscle were analysed, as this knowledge could prove beneficial in
the generation of more translatable animal models and therapies.
To evaluate whether changes at the NMJ as predicted from mouse models
also occurred in humans with muscle wasting, NMJ morphology was
compared between patients with cancer cachexia, weight stable cancer
patients, and control patients. Surgical muscle biopsies were sampled, NMJs
were immunofluorescently visualised, imaged and analysed using âaNMJ-morphâ, a semi-automated macro version built upon the well-established
workflow âNMJ-morphâ. Whilst cancer cachectic patients showed clear signs
of muscle atrophy, NMJ morphology was found to be stable with no signs of
denervation. This suggests that current mouse models of cancer cachexia,
modelling denervation, should be translated with caution. Given the stark differences between mouse and human NMJs in health and
disease, the development of more suitable animal models is fundamental.
Therefore, exploration of NMJ morphology across other mammalian species
(cat, dog, sheep, pig, and pony) in comparison to the human was required.
Overall, sheep and pig proved to be the most similar to human NMJ
morphology across pelvic/lower limb muscles, making them attractive models
to explore further.
Whilst it is advantageous to explore other mammalian models, it is ultimately
critical to better understand the human NMJ in health and disease in order to
mimic disease appropriately, regardless of model. The ageing related loss of
muscle mass and function, sarcopenia, is a major public health problem and
it is thus important to evaluate molecular pathways that occur during healthy
ageing at the level of both muscle and the NMJ. Whilst much is known about
the ageing of human muscle, the molecular pathways governing healthy
ageing at the NMJ itself remain unexplored. This project shows that in
comparison to âMiddle agedâ subjects (40 yo â50 yo), the muscle (devoid of
the NMJ) of âSeniorâ (60 yo) and âOldâ (70 yo â80 yo) subjects is in an insulin
resistant state, with dysregulation of pathways associated with oxidative
phosphorylation and energy production. NMJ-enriched samples of Senior
and Old subjects are more similar to Middle aged subjects in protein
abundance, and pathways associated with insulin sensitivity are upregulated.
Overall, this project emphasizes the stark morphological difference between
NMJs of the mouse and the human, or other mammals. In particular the
stability of the human NMJ during muscle wasting diseases such as cancer
cachexia, or on a molecular level, during ageing, is striking. Therefore, there
is an unmet need to find animal models that are more suitable to model
human diseases. This project found that the sheep and pig are suitable to be
explored as models of human neuromuscular diseases, opening up avenues
of research towards more translatable larger mammalian models
Recognising the potential of large animals for modelling neuromuscular junction physiology and disease
The aetiology and pathophysiology of many diseases of the motor unit remain poorly understood and the role of the neuromuscular junction (NMJ) in this group of disorders is particularly overlooked, especially in humans, when these diseases are comparatively rare. However, elucidating the development, function and degeneration of the NMJ is essential to uncover its contribution to neuromuscular disorders, and to explore potential therapeutic avenues to treat these devastating diseases. Until now, an understanding of the role of the NMJ in disease pathogenesis has been hindered by inherent differences between rodent and human NMJs: stark contrasts in body size and corresponding differences in associated axon length underpin some of the translational issues in animal models of neuromuscular disease. Comparative studies in large mammalian models, including examination of naturally occurring, highly prevalent animal diseases and evaluation of their treatment, might provide more relevant insights into the pathogenesis and therapy of equivalent human diseases. This review argues that large animal models offer great potential to enhance our understanding of the neuromuscular system in health and disease, and in particular, when dealing with diseases for which nerve length dependency might underly the pathogenesis
Gene Ontology (GO)-driven inference of candidate proteomic markers associated with muscle atrophy conditions
This research was funded by a grant from Highlands & Islands Enterprise, UK (AS and HH).Skeletal muscle homeostasis is essential for the maintenance of a healthy and active lifestyle. Imbalance in muscle homeostasis has significant consequences such as atrophy, loss of muscle mass, and progressive loss of functions. Aging-related muscle wasting, sarcopenia, and atrophy as a consequence of disease, such as cachexia, reduce the quality of life, increase morbidity and result in an overall poor prognosis. Investigating the muscle proteome related to muscle atrophy diseases has a great potential for diagnostic medicine to identify (i) potential protein biomarkers, and (ii) biological processes and functions common or unique to muscle wasting, cachexia, sarcopenia, and aging alone. We conducted a meta-analysis using gene ontology (GO) analysis of 24 human proteomic studies using tissue samples (skeletal muscle and adipose biopsies) and/or biofluids (serum, plasma, urine). Whilst there were few similarities in protein directionality across studies, biological processes common to conditions were identified. Here we demonstrate that the GO analysis of published human proteomics data can identify processes not revealed by single studies. We recommend the integration of proteomics data from tissue samples and biofluids to yield a comprehensive overview of the human skeletal muscle proteome. This will facilitate the identification of biomarkers and potential pathways of muscle-wasting conditions for use in clinics.Peer reviewe
Gene ontology (GO)-driven inference of candidate proteomic markers associated with muscle atrophy conditions
Skeletal muscle homeostasis is essential for the maintenance of a healthy and active lifestyle. Imbalance in muscle homeostasis has significant consequences such as atrophy, loss of muscle mass, and progressive loss of functions. Aging-related muscle wasting, sarcopenia, and atrophy as a consequence of disease, such as cachexia, reduce the quality of life, increase morbidity and result in an overall poor prognosis. Investigating the muscle proteome related to muscle atrophy diseases has a great potential for diagnostic medicine to identify (i) potential protein biomarkers, and (ii) biological processes and functions common or unique to muscle wasting, cachexia, sarcopenia, and aging alone. We conducted a meta-analysis using gene ontology (GO) analysis of 24 human proteomic studies using tissue samples (skeletal muscle and adipose biopsies) and/or biofluids (serum, plasma, urine). Whilst there were few similarities in protein directionality across studies, biological processes common to conditions were identified. Here we demonstrate that the GO analysis of published human proteomics data can identify processes not revealed by single studies. We recommend the integration of proteomics data from tissue samples and biofluids to yield a comprehensive overview of the human skeletal muscle proteome. This will facilitate the identification of biomarkers and potential pathways of muscle-wasting conditions for use in clinics
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Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility.
To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry
Observing glacier elevation changes from spaceborne optical and radar sensors â an inter-comparison experiment using ASTER and TanDEM-X data
Observations of glacier mass changes are key to understanding the response of glaciers to climate change and related impacts, such as regional runoff, ecosystem changes, and global sea-level rise. Spaceborne optical and radar sensors make it possible to quantify glacier elevation changes, and thus multi-annual mass changes, on a regional and global scale. However, estimates from a growing number of studies show a wide range of results with differences often beyond uncertainty bounds. Here, we present the outcome of a community-based inter-comparison experiment using spaceborne optical stereo (ASTER) and synthetic aperture radar interferometry (TanDEM-X) data to estimate elevation changes for defined glaciers and target periods that pose different assessment challenges. Using provided or self-processed digital elevation models (DEMs) for five test sites, 12 research groups provided a total of 97 spaceborne elevation-change datasets using various processing strategies. Validation with airborne data showed that using an ensemble estimate is promising to reduce random errors from different instruments and processing methods, but still requires a more comprehensive investigation and correction of systematic errors. We found that scene selection, DEM processing, and co-registration have the biggest impact on the results. Other processing steps, such as treating spatial data voids, differences in survey periods, or radar penetration, can still be important for individual cases. Future research should focus on testing different implementations of individual processing steps (e.g. co-registration) and addressing issues related to temporal corrections, radar penetration, glacier area changes, and density conversion. Finally, there is a clear need for our community to develop best practices, use open, reproducible software, and assess overall uncertainty in order to enhance inter-comparison and empower physical process insights across glacier elevation-change studies
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