scholarly journals Plum is a novel regulator of synaptic function and muscle size in D. melanogaster

2018 ◽  
Author(s):  
Hrvoje Augustin ◽  
Jereme G. Spiers ◽  
Nathaniel S. Woodling ◽  
Joern R. Steinert ◽  
Linda Partridge
Keyword(s):  
Body Weight ◽  
Neuromuscular Junction ◽  
Synaptic Function ◽  
Negative Regulator ◽  
Therapeutic Interventions ◽  
Muscle Size ◽  
Model Organisms ◽  
Neuromuscular System ◽  
Age Related ◽  
And Function

ABSTRACTAlterations in the neuromuscular system underlie several neuromuscular diseases and play critical roles in the development of sarcopenia, the age-related loss of muscle mass and function. Mammalian Myostatin (MST) and GDF11, members of the TGF-β superfamily of growth factors, are powerful regulators of muscle size in both model organisms and humans. Myoglianin (MYO), the Drosophila homolog of MST and GDF11, is a strong inhibitor of synaptic function and structure at the neuromuscular junction (NMJ), and a negative regulator of body weight and muscle size and function in flies. Here, we identified Plum, a cell surface immunoglobulin homologous to mammalian developmental regulators Protogenin and Nope, as a modulator of MYO function in the larval neuromuscular system. Reduction of Plum specifically in the larval body-wall muscles abolishes the previously demonstrated positive effect of attenuated MYO signalling on both muscle size and neuromuscular junction structure and function, likely by de-sequestrating the remaining MYO. In addition, downregulation of Plum on its own results in decreased synaptic strength and body weight, classifying Plum as a (novel) regulator of neuromuscular function and body (muscle) size. These findings offer new insights into possible regulatory mechanisms behind ageing- and disease-related neuromuscular dysfunctions in humans and identify potential targets for therapeutic interventions.

scholarly journals Molecular and phenotypic analysis of rodent models reveals conserved and species-specific modulators of human sarcopenia

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Anastasiya Börsch ◽  
Daniel J. Ham ◽  
Nitish Mittal ◽  
Lionel A. Tintignac ◽  
Eugenia Migliavacca ◽  
...  
Keyword(s):  
Muscle Mass ◽  
Inflammatory Responses ◽  
Molecular Data ◽  
Model Organisms ◽  
Sequencing Data ◽  
Phenotypic Analysis ◽  
Age Related ◽  
Analogous Data ◽  
Species Specific ◽  
And Function

AbstractSarcopenia, the age-related loss of skeletal muscle mass and function, affects 5–13% of individuals aged over 60 years. While rodents are widely-used model organisms, which aspects of sarcopenia are recapitulated in different animal models is unknown. Here we generated a time series of phenotypic measurements and RNA sequencing data in mouse gastrocnemius muscle and analyzed them alongside analogous data from rats and humans. We found that rodents recapitulate mitochondrial changes observed in human sarcopenia, while inflammatory responses are conserved at pathway but not gene level. Perturbations in the extracellular matrix are shared by rats, while mice recapitulate changes in RNA processing and autophagy. We inferred transcription regulators of early and late transcriptome changes, which could be targeted therapeutically. Our study demonstrates that phenotypic measurements, such as muscle mass, are better indicators of muscle health than chronological age and should be considered when analyzing aging-related molecular data.

scholarly journals Potential Benefits of a Minimal Dose Eccentric Resistance Training Paradigm to Combat Sarcopenia and Age-Related Muscle and Physical Function Deficits in Older Adults

2021 ◽  
Vol 12 ◽  
Author(s):  
Sara A. Harper ◽  
Brennan J. Thompson
Keyword(s):  
Older Adults ◽  
Resistance Training ◽  
Functional Performance ◽  
Functional Decline ◽  
Therapeutic Interventions ◽  
Training Paradigm ◽  
Exercise Participation ◽  
Minimal Dose ◽  
Age Related ◽  
And Function

The ability of older adults to perform activities of daily living is often limited by the ability to generate high mechanical outputs. Therefore, assessing and developing maximal neuromuscular capacity is essential for determining age-related risk for functional decline as well as the effectiveness of therapeutic interventions. Interventions designed to enhance neuromuscular capacities underpinning maximal mechanical outputs could positively impact functional performance in daily life. Unfortunately, < 10% of older adults meet the current resistance training guidelines. It has recently been proposed that a more “minimal dose” RT model may help engage a greater proportion of older adults, so that they may realize the benefits of RT. Eccentric exercise offers some promising qualities for such an approach due to its efficiency in overloading contractions that can induce substantial neuromuscular adaptations. When used in a minimal dose RT paradigm, eccentric-based RT may be a particularly promising approach for older adults that can efficiently improve muscle mass, strength, and functional performance. One approach that may lead to improved neuromuscular function capacities and overall health is through heightened exercise tolerance which would favor greater exercise participation in older adult populations. Therefore, our perspective article will discuss the implications of using a minimal dose, submaximal (i.e., low intensity) multi-joint eccentric resistance training paradigm as a potentially effective, and yet currently underutilized, means to efficiently improve neuromuscular capacities and function for older adults.

scholarly journals Neurexin–Neuroligin 1 regulates synaptic morphology and functions via the WAVE regulatory complex in Drosophila neuromuscular junction

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Guanglin Xing ◽  
Moyi Li ◽  
Yichen Sun ◽  
Menglong Rui ◽  
Yan Zhuang ◽  
...  
Keyword(s):  
Neuromuscular Junction ◽  
Molecular Mechanisms ◽  
Postsynaptic Membrane ◽  
Synaptic Function ◽  
Actin Assembly ◽  
Actin Reorganization ◽  
Synaptic Structure ◽  
Structural And Functional Properties ◽  
Regulatory Complex ◽  
And Function

Neuroligins are postsynaptic adhesion molecules that are essential for postsynaptic specialization and synaptic function. But the underlying molecular mechanisms of neuroligin functions remain unclear. We found that Drosophila Neuroligin 1 (DNlg1) regulates synaptic structure and function through WAVE regulatory complex (WRC)-mediated postsynaptic actin reorganization. The disruption of DNlg1, DNlg2, or their presynaptic partner neurexin (DNrx) led to a dramatic decrease in the amount of F-actin. Further study showed that DNlg1, but not DNlg2 or DNlg3, directly interacts with the WRC via its C-terminal interacting receptor sequence. That interaction is required to recruit WRC to the postsynaptic membrane to promote F-actin assembly. Furthermore, the interaction between DNlg1 and the WRC is essential for DNlg1 to rescue the morphological and electrophysiological defects in dnlg1 mutants. Our results reveal a novel mechanism by which the DNrx-DNlg1 trans-synaptic interaction coordinates structural and functional properties at the neuromuscular junction.

scholarly journals Age-Related Alterations at Neuromuscular Junction: Role of Oxidative Stress and Epigenetic Modifications

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1307
Author(s):  
Gabriella Dobrowolny ◽  
Alessandra Barbiera ◽  
Gigliola Sica ◽  
Bianca Maria Scicchitano
Keyword(s):  
Neuromuscular Junction ◽  
Neuromuscular Junctions ◽  
Epigenetic Modifications ◽  
Neuromuscular System ◽  
Molecular Alterations ◽  
Age Related ◽  
Fiber Number ◽  
Physical Abilities ◽  
Effects Of Aging

With advancing aging, a decline in physical abilities occurs, leading to reduced mobility and loss of independence. Although many factors contribute to the physio-pathological effects of aging, an important event seems to be related to the compromised integrity of the neuromuscular system, which connects the brain and skeletal muscles via motoneurons and the neuromuscular junctions (NMJs). NMJs undergo severe functional, morphological, and molecular alterations during aging and ultimately degenerate. The effect of this decline is an inexorable decrease in skeletal muscle mass and strength, a condition generally known as sarcopenia. Moreover, several studies have highlighted how the age-related alteration of reactive oxygen species (ROS) homeostasis can contribute to changes in the neuromuscular junction morphology and stability, leading to the reduction in fiber number and innervation. Increasing evidence supports the involvement of epigenetic modifications in age-dependent alterations of the NMJ. In particular, DNA methylation, histone modifications, and miRNA-dependent gene expression represent the major epigenetic mechanisms that play a crucial role in NMJ remodeling. It is established that environmental and lifestyle factors, such as physical exercise and nutrition that are susceptible to change during aging, can modulate epigenetic phenomena and attenuate the age-related NMJs changes. This review aims to highlight the recent epigenetic findings related to the NMJ dysregulation during aging and the role of physical activity and nutrition as possible interventions to attenuate or delay the age-related decline in the neuromuscular system.

scholarly journals Presynaptic depression maintains stable synaptic strength in developmentally arrested Drosophila larvae

2019 ◽  
Author(s):  
Sarah Perry ◽  
Pragya Goel ◽  
Daniel Miller ◽  
Barry Ganetzky ◽  
Dion Dickman
Keyword(s):  
Neuromuscular Junction ◽  
Time Scales ◽  
Life Stage ◽  
Synaptic Strength ◽  
Muscle Size ◽  
Synaptic Growth ◽  
Long Time ◽  
Presynaptic Release ◽  
And Function ◽  
Synaptic Structures

ABSTRACTPositive and negative modes of regulation typically constrain synaptic growth and function within narrow physiological ranges. However, it is unclear how synaptic strength is maintained when both pre- and post-synaptic compartments continue to grow beyond stages imposed by typical developmental programs. To address whether and how synapses can adjust to a novel life stage for which they were never molded by evolution, we have characterized synaptic growth, structure and function at the Drosophila neuromuscular junction (NMJ) under conditions where larvae are terminally arrested at the third instar stage. While wild type larvae transition to pupae after 5 days, arrested third instar (ATI) larvae persist for up to 35 days, during which NMJs exhibit extensive overgrowth in muscle size, presynaptic release sites, and postsynaptic glutamate receptors. Remarkably, despite this exuberant growth of both pre- and post-synaptic structures, stable neurotransmission is maintained throughout the ATI lifespan through a potent homeostatic reduction in presynaptic neurotransmitter release. Arrest of the larval stage in stathmin mutants reveals a degree of progressive instability and neurodegeneration that was not apparent during the typical larval period. Hence, during a period of unconstrained synaptic growth through an extended developmental period, a robust and adaptive form of presynaptic homeostatic depression can stabilize neurotransmission. More generally, the ATI manipulation provides an attractive system for studying neurodegeneration and plasticity across longer time scales.SIGNIFICANCE STATEMENTIt is unclear whether and how synapses adjust to a novel life stage for which they were never molded by evolution. We have characterized synaptic plasticity at the Drosophila neuromuscular junction in third instar larvae arrested in development for over 35 days. This approach has revealed that homeostatic depression stabilizes synaptic strength throughout the life of arrested third instars to compensate for excessive pre- and post-synaptic growth. This system also now opens the way for the study of synapses and degeneration over long time scales in this powerful model synapse.

scholarly journals Comparative study of protein aggregation propensity and mutation tolerance between naked mole-rat and mouse

2021 ◽  
Author(s):  
Savandara Besse ◽  
Raphaël Poujol ◽  
Julie G. Hussin
Keyword(s):  
Healthy Aging ◽  
Molecular Mechanisms ◽  
Therapeutic Interventions ◽  
Model Organisms ◽  
Protein Homeostasis ◽  
Aggregation Propensity ◽  
Age Related ◽  
Mole Rat ◽  
Significant Difference ◽  
Naked Mole Rat

The molecular mechanisms of aging and life expectancy have been studied in model organisms with short lifespans. However, long-lived species may provide insights into successful strategies of healthy aging, potentially opening the door for novel therapeutic interventions in age-related diseases. Notably, naked mole-rats, the longest-lived rodent, present attenuated aging phenotypes in comparison to mice. Their resistance toward oxidative stress has been proposed as one hallmark of their healthy aging, suggesting their ability to maintain cell homeostasis, and specifically their protein homeostasis. To identify the general principles behind their protein homeostasis robustness, we compared the aggregation propensity and mutation tolerance of naked mole-rat and mouse orthologous proteins. Our analysis showed no proteome-wide differential effects in aggregation propensity and mutation tolerance between these species, but several subsets of proteins with a significant difference in aggregation propensity. We found an enrichment of proteins with higher aggregation propensity in naked mole-rat involved the inflammasome complex, and in nucleic acid binding. On the other hand, proteins with lower aggregation propensity in naked mole-rat have a significantly higher mutation tolerance compared to the rest of the proteins. Among them, we identified proteins known to be associated with neurodegenerative and age-related diseases. These findings highlight the intriguing hypothesis about the capacity of the naked mole-rat proteome to delay aging through its proteomic intrinsic architecture.

scholarly journals Skeletal muscle mitochondrial respiration in a model of age-related osteoarthritis is impaired after dietary rapamycin

2021 ◽  
Author(s):  
Christian J Elliehausen ◽  
Dennis M Minton ◽  
Alexander D Nichol ◽  
Adam R Konopka
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Function ◽  
Mitochondrial Respiration ◽  
Guinea Pigs ◽  
Muscle Size ◽  
Skeletal Muscle Mitochondria ◽  
Age Related ◽  
End Stage ◽  
And Function ◽  
Permeabilized Muscle

A decline in skeletal muscle mitochondrial function is associated with the loss of skeletal muscle size and function during knee osteoarthritis (OA). We have recently reported that the 12-weeks of dietary rapamycin (Rap, 14ppm), with or without metformin (Met, 1000ppm), increased plasma glucose and OA severity in male Dunkin Hartley (DH) guinea pigs, a model of naturally occurring, age-related OA. The purpose of the current study was to determine if increased OA severity after dietary Rap and Rap+Met was accompanied by impaired skeletal muscle mitochondrial function. Mitochondrial respiration and hydrogen peroxide (H2O2) emissions were evaluated in permeabilized muscle fibers via high-resolution respirometry and fluorometry using either a saturating bolus or titration of ADP. Rap and Rap+Met decreased complex I (CI)-linked respiration and increased ADP sensitivity, consistent with previous findings in patients with end-stage OA. Rap also tended to decrease mitochondrial H2O2 emissions, however, this was no longer apparent after normalizing to respiration. The decrease in CI-linked respiration was accompanied with lower CI protein abundance. This is the first inquiry into how lifespan extending treatments Rap and Rap+Met can influence skeletal muscle mitochondria in a model of age-related OA. Collectively, our data suggest that Rap with or without Met inhibits CI-linked capacity and increases ADP sensitivity in DH guinea pigs that have greater OA severity.

scholarly journals Changes of mitochondrial ultrastructure and function during ageing in mice and Drosophila

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Tobias Brandt ◽  
Arnaud Mourier ◽  
Luke S Tain ◽  
Linda Partridge ◽  
Nils-Göran Larsson ◽  
...  
Keyword(s):  
Functional Decline ◽  
Model Organisms ◽  
Mouse Heart ◽  
Inner Membrane ◽  
Membrane Morphology ◽  
Age Related ◽  
Ultrastructure And Function ◽  
And Function ◽  
The Impact ◽  
Age Related Changes

Ageing is a progressive decline of intrinsic physiological functions. We examined the impact of ageing on the ultrastructure and function of mitochondria in mouse and fruit flies (Drosophila melanogaster) by electron cryo-tomography and respirometry. We discovered distinct age-related changes in both model organisms. Mitochondrial function and ultrastructure are maintained in mouse heart, whereas subpopulations of mitochondria from mouse liver show age-related changes in membrane morphology. Subpopulations of mitochondria from young and old mouse kidney resemble those described for apoptosis. In aged flies, respiratory activity is compromised and the production of peroxide radicals is increased. In about 50% of mitochondria from old flies, the inner membrane organization breaks down. This establishes a clear link between inner membrane architecture and functional decline. Mitochondria were affected by ageing to very different extents, depending on the organism and possibly on the degree to which tissues within the same organism are protected against mitochondrial damage.

scholarly journals The histone demethylase KDM5 is required for synaptic structure and function at the Drosophila neuromuscular junction

2020 ◽  
Author(s):  
Helen M. Belalcazar ◽  
Emily L. Hendricks ◽  
Sumaira Zamurrad ◽  
Faith L.W. Liebl ◽  
Julie Secombe
Keyword(s):  
Neuromuscular Junction ◽  
Histone Demethylase ◽  
Synaptic Function ◽  
Complex Nature ◽  
Synaptic Structure ◽  
Genes Encoding ◽  
Demethylase Activity ◽  
Larval Neuromuscular Junction ◽  
And Function ◽  
Structure And Activity

SummaryMutations in the genes encoding the KDM5 family of histone demethylases are observed in individuals with intellectual disability (ID). Despite clear evidence linking KDM5 function to neurodevelopmental pathways, how this family of proteins impacts transcriptional programs to mediate synaptic structure and activity remains unclear. Using the Drosophila larval neuromuscular junction (NMJ), we show that KDM5 is required for neuroanatomical development and synaptic function. The JmjC-domain encoded histone demethylase activity of KDM5, which is expected to be diminished by many ID-associated alleles and required for appropriate synaptic morphology and neurotransmission. The C5HC2 zinc finger of KDM5 is also involved, as an ID-associated mutation in this motif reduces NMJ bouton number but increases bouton size. KDM5 therefore uses demethylase-dependent and independent mechanisms to regulate NMJ structure and activity, highlighting the complex nature by which this chromatin modifier carries out its neuronal gene regulatory programs.

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