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Myokines and exosomes, originating from skeletal muscle, are shown to play a significant role in maintaining brain homeostasis. While exercise has been reported to promote muscle secretion, little is known about the effects of neuronal innervation and activity on the yield and molecular composition of biologically active molecules from muscle. As neuromuscular diseases and disabilities associated with denervation impact muscle metabolism, we hypothesize that neuronal innervation and firing may play a pivotal role in regulating secretion activities of skeletal muscles. We examined this hypothesis using an engineered neuromuscular tissue model consisting of skeletal muscles innervated by motor neurons. The innervated muscles displayed elevated expression of mRNAs encoding neurotrophic myokines, such as interleukin-6, brain-derived neurotrophic factor, and FDNC5, as well as the mRNA of peroxisome-proliferator-activated receptor γ coactivator 1α, a key regulator of muscle metabolism. Upon glutamate stimulation, the innervated muscles secreted higher levels of irisin and exosomes containing more diverse neurotrophic microRNAs than neuron-free muscles. Consequently, biological factors secreted by innervated muscles enhanced branching, axonal transport, and, ultimately, spontaneous network activities of primary hippocampal neurons in vitro. Overall, these results reveal the importance of neuronal innervation in modulating muscle-derived factors that promote neuronal function and suggest that the engineered neuromuscular tissue model holds significant promise as a platform for producing neurotrophic molecules.
Free, publicly-accessible full text available May 7, 2025 -
Growing evidence supports the confident association between distinct amyloid beta (Aβ) isoforms and Alzheimer's Disease (AD) pathogenesis. As such, critical investigations seeking to uncover the translational factors contributing to Aβ toxicity represent a venture of significant value. Herein, we comprehensively assess full-length Aβ42 stereochemistry, with a specific focus on models that consider naturally-occurring isomerization of Asp and Ser residues. We customize various forms of d -isomerized Aβ as natural mimics, ranging from fragments containing a single d residue to full length Aβ42 that includes multiple isomerized residues, systematically evaluating their cytotoxicity against a neuronal cell line. Combining multidimensional ion mobility-mass spectrometry experimental data with replica exchange molecular dynamics simulations, we confirm that co- d -epimerization at Asp and Ser residues within Aβ42 in both N-terminal and core regions effectively reduces its cytotoxicity. We provide evidence that this rescuing effect is associated with the differential and domain-specific compaction and remodeling of Aβ42 secondary structure.more » « less
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Metabolomics, the study of metabolites present in biological samples, can provide a global view of sample state as well as insights into biological changes caused by disease or environmental interactions. Mass spectrometry (MS) is commonly used for metabolomics analysis given its high-throughput capabilities, high sensitivity, and capacity to identify multiple compounds in complex samples simultaneously. MS can be coupled to separation methods that can handle small volumes, making it well suited for analyzing the metabolome of organoids, miniaturized three-dimensional aggregates of stem cells that model in vivo organs. Organoids are being used in research efforts to study human disease and development, and in the design of personalized drug treatments. For organoid models to be useful, they need to recapitulate morphological and chemical aspects, such as the metabolome, of the parent tissue. This review highlights the separation- and imaging-based MS-based metabolomics methods that have been used to analyze the chemical contents of organoids. Future perspectives on how MS techniques can be optimized to determine the accuracy of organoid models and expand the field of organoid research are also discussed.more » « less
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Neuropeptides (NPs), a unique class of neuronal signaling molecules, participate in a variety of physiological processes and diseases. Quantitative measurements of NPs provide valuable information regarding how these molecules are differentially regulated in a multitude of neurological, metabolic, and mental disorders. Mass spectrometry (MS) has evolved to become a powerful technique for measuring trace levels of NPs in complex biological tissues and individual cells using both targeted and exploratory approaches. There are inherent challenges to measuring NPs, including their wide endogenous concentration range, transport and postmortem degradation, complex sample matrices, and statistical processing of MS data required for accurate NP quantitation. This review highlights techniques developed to address these challenges and presents an overview of quantitative MS-based measurement approaches for NPs, including the incorporation of separation methods for high-throughput analysis, MS imaging for spatial measurements, and methods for NP quantitation in single neurons.more » « less