Biology subjects

Kikuchi, Y.

Publications and source records attributed to Kikuchi, Y..

34 records · Page 2Linked to original sources

bioRxiv2023

Transposon sequencing reveals the essential gene set and genes enabling gut symbiosis in the insect symbiont Caballeronia insecticola

Caballeronia insecticola is a bacterium belonging to the Burkholderia genus sensu lato, able to colonize multiple environments like soils and the gut of the bean bug Riptortus pedestris. To identify the essential genome of a bacterium is a first step in the understanding of its lifestyles. We constructed a saturated Himar1 mariner transposon library and revealed by transposon-sequencing (Tn-seq) that 498 protein-coding genes constitute the essential genome of C. insecticola for growth in free-living conditions. By comparing essential gene sets of C. insecticola and seven related Burkholderia s.l. strains, only 120 common genes were identified indicating that a large part of the essential genome is strain-specific. In order to reproduce specific nutritional conditions that are present in the gut of R. pedestris, we grew the mutant library in minimal media supplemented with candidate gut nutrients and identified several condition-dependent fitness-defect genes by Tn-seq. To validate the robustness of the approach, insertion mutants in six fitness genes were constructed and their growth-deficiency in media supplemented with the corresponding nutrient was confirmed. The mutants were further tested for their efficiency in R. pedestris gut colonization, confirming that gluconeogenic carbon sources, taurine and inositol, are nutrients consumed by the symbiont in the gut.

microbiology↗

bioRxiv2022

Immediate neural network impact after the loss of a semantic hub

The human brain extracts meaning from the world using an extensive neural system for semantic knowledge. Whether such broadly distributed systems1-3 crucially depend on or can compensate for the loss of one of their highly interconnected hubs4-6 is controversial4. The strongest level of causal evidence for the role of a brain hub is to evaluate its acute network-level impact following disconnection and any rapid functional compensation that ensues. We report rare neurophysiological data from two patients who underwent awake intracranial recordings during a speech prediction task immediately before and after neurosurgical treatment that required disconnection of the left anterior temporal lobe (ATL), a crucial hub for semantic knowledge4-6. Informed by a predictive coding framework, we tested three sets of hypotheses including diaschisis causing disruption in interconnected sites7 and incomplete or complete compensation by other language-critical and speech processing sites8-10. Immediately after ATL disconnection, we observed highly specific neurophysiological alterations in the recorded fronto-temporal network, including abnormally magnified high gamma responses to the speech sounds in auditory cortex. We also observed evidence for rapid compensation, seen as focal increases in effective connectivity involving language-critical sites in the inferior frontal gyrus and speech processing sites in auditory cortex. However, compensation was incomplete, in part because after ATL disconnection speech prediction signals were depleted in auditory cortex. This study provides direct causal evidence for a semantic hub in the human brain and shows striking neural impact and a rapid attempt at compensation in a neural network after the loss of one of its hubs.

neuroscience↗

bioRxiv2022

Pulmonary dust foci as rat pneumoconiosis lesion induced by titanium dioxide nanoparticles in 13-week inhalation study

BackgroundMost toxicological studies on titanium dioxide (TiO2) particles to date have concentrated on carcinogenicity and acute toxicity, with few studies focusing of pneumoconiosis, which is a variety of airspace and interstitial lung diseases caused by particle-laden macrophages. The present study examined rat pulmonary lesions associated with pneumoconiosis after inhalation exposure to TiO2 nanoparticles (NPs). MethodsMale and female F344 rats were exposed to 6.3, 12.5, 25, or 50 mg/m3 anatase type TiO2 NPs for 6 hours/day, 5 days/week for 13 weeks using a whole-body inhalation exposure system. After the last exposure the rats were euthanized and blood, bronchoalveolar lavage fluid, and all tissues including lungs and mediastinal lymph nodes were collected and subjected to biological and histopathological analyses. ResultsNumerous milky white spots were present in the lungs after exposure 25 and 50 mg/m3 TiO2 NPs. Histopathological analysis revealed that the spots were alveolar lesions, characterized predominantly by the agglomeration of particle-laden macrophages and the presence of reactive alveolar epithelial type 2 cell (AEC2) hyperplasia. We defined this characteristic lesion as pulmonary dust foci (PDF). The PDF is an inflammatory niche, with decreased vascular endothelial cells in the interstitium, and proliferating AEC2 transformed into alveolar epithelial progenitor cells. The AEC2 in the PDF had acquired DNA damage. Based on PDF induction, the lowest observed adverse effect concentration for pulmonary disorders in male and female rats in this study was 12.5 mg/m3 and 6.3 mg/m3, respectively. The no observed adverse effect concentration for male rats was 6.3 mg/m3. There was a sex difference in lung lesion development, with females showing more pronounced lesion parameters than males. ConclusionsInhalation exposure to TiO2 NPs caused PDF, an air-space lesion which is an alveolar inflammatory niche containing particle-laden macrophages and proliferating AEC2. This PDF histopathologically resembles some pneumoconiosis lesions (pulmonary siderosis and hard metal pneumoconiosis) in workers and lung disease in smokers, suggesting that it is an early pneumoconiosis lesion caused by exposure to TiO2 NPs in rats and a common alveolar reaction in mammals.

pathology↗

bioRxiv2021

Dose-response relationship of pulmonary disorders by inhalation exposure to cross-linked water-soluble acrylic acid polymers in F344 rats

BackgroundIn Japan, six workers handling cross-linked water-soluble acrylic acid polymer (CWAAP) at a chemical plant suffered from lung diseases, including fibrosis, interstitial pneumonia, emphysema, and pneumothorax. We recently demonstrated that inhalation of CWAAP-A, one type of CWAAP, causes pulmonary disorders in rats. It is important to investigate dose-response relationships and recoverability from exposure to CWAAPs for establishing occupational health guidelines, such as setting threshold limit value for CWAAPs in the workplace. MethodsMale and female F344 rats were exposed to 0.3, 1, 3, or 10 mg/m3 CWAAP-A for 6 hours/day, 5 days/week for 13 weeks using a whole-body inhalation exposure system. At 1 hour, 4 weeks, and 13 weeks after the last exposure the rats were euthanized and blood, bronchoalveolar lavage fluid, and all tissues including lungs and mediastinal lymph nodes were collected and subjected to biological and histopathological analyses. In a second experiment, male rats were pre-treated with clodronate liposome or polymorphonuclear leukocyte-neutralizing antibody to deplete macrophages or neutrophils, respectively, and exposed to CWAAP-A for 6 hours/day for 2 days. ResultsCWAAP-A exposure damaged only the alveoli. The lowest observed adverse effect concentration (LOAEC) was 1 mg/m3 and the no observed adverse effect concentration (NOAEC) was 0.3 mg/m3. Rats of both sexes were able to recover from the tissue damage caused by 13 weeks exposure to 1 mg/m3 CWAAP-A. In contrast, tissue damage caused by exposure to 3 and 10 mg/m3 was irreversible due to the development of interstitial lung lesions. There was a gender difference in the recovery from CWAAP-A induced pulmonary disorders, with females recovering less than males. Finally, acute lung effects caused by CWAAP-A were significantly reduced by depletion of alveolar macrophages. ConclusionsPulmonary damage caused by inhalation exposure to CWAAP-A was dose-dependent, specific to the lung and lymph nodes, and acute lung damage was ameliorated by depleting macrophages in the lungs. CWAAP-A had both a LOAEC and a NOAEC, and tissue damage caused by exposure to 1 mg/m3 CWAAP-A was reversible: recovery in female rats was less than for males. These findings indicate that concentration limits for CWAAPs in the workplace can be determined.

pharmacology and toxicology↗

bioRxiv2021

Lack of pulmonary fibrogenicity and carcinogenicity of titanium dioxide nanoparticles in 26-week inhalation study in rasH2 mouse model

BackgroundWith the rapid development of alternative methods based on the spirit of animal welfare, the publications of animal studies evaluating endpoints such as cancer have been extremely reduced. There have been no systemic inhalation exposure studies of titanium dioxide nanoparticles (TiO2 NPs) using CByB6F1-Tg(HRAS)2Jic (rasH2) 26-week study mice model for detecting carcinogenicity. MethodsMale and female rasH2 mice were exposed to 2, 8 or 32 mg/m3 of TiO2 NPs for 6 hours/day, 5 days/week for 26 weeks using a whole-body inhalation exposure system, with reference to the Organization for Economic Co-operation and Development principles of Good Laboratory Practice. All tissues including lungs, and blood were collected and subjected to biological and histopathological analyses. Additionally, Ki67 positive index were evaluated in mice lung alveolar epithelial type 2 cell (AEC2). ResultsThis study established a stable method for generating and exposing TiO2 NPs aerosol, and clarified the dose-response relationship by TiO2 NPs inhalation to rasH2 mice. TiO2 NPs exposure induced deposition of particles in lungs and mediastinal lymph nodes in a dose-dependent manner in each exposure group. Additionally, alveolar inflammation was only observed in 32 mg/m3 exposure group in both the sexes. Exposure to TiO2 NPs, as well as other organs, did not increase the incidence of lung tumors in any group, and pulmonary fibrosis and pre-neoplastic lesions were not observed in all groups. Finally, the cell proliferative activity of AEC2 was examined, and it was not increased by exposure to TiO2 NPs. ConclusionsThis is the first report showing the lack of pulmonary fibrogenicity and carcinogenicity (no evidence of carcinogenic activity) of TiO2 NPs in 26-week inhalation study in rasH2 mice exposed up to 32 mg/m3, which is considered to be a high concentration. Macrophages undergoing phagocytosis due to TiO2 NPs exposure formed inflammatory foci in the alveolar regions of exposed mice but did not develop fibrosis or hyperplasia or tumors. Moreover, the cell proliferative ability of AEC2 in lesions was not increased. In addition, no carcinogenicity was observed for any organs other than the lungs in this study.

pharmacology and toxicology↗

bioRxiv2021

Interpersonal brain synchronization during face-to-face economic exchange between acquainted dyads

Interpersonal brain synchronization (IBS) has been observed during social interactions and involves various factors, such as familiarity with the partner and type of social activity. A previous study has shown that face-to-face interactions in pairs of strangers increase IBS. However, it is unclear whether this can be observed when the nature of the interacting partners is different. Herein, we aimed to extend these findings to pairs of acquaintances. Neural activity in the frontal and temporal regions was recorded using functional near-infrared spectroscopy hyperscanning. Participants played an ultimatum game that required virtual economic exchange in two experimental settings: the face-to-face and face-blocked conditions. Random pair analysis confirmed whether IBS was induced by social interaction. Contrary to the aforementioned study, our results did not show any cooperative behavior or task-induced IBS increase. Conversely, the random pair analysis results revealed that the pair-specific IBS was significant only in the task condition at the left and right superior frontal, middle frontal, orbital superior frontal, right superior temporal, precentral, and postcentral gyri. Our results revealed that face-to-face interaction in acquainted pairs did not increase IBS and supported the idea that IBS is affected by "with whom we interact and how."

neuroscience↗

bioRxiv2021

Pathological characteristics of pulmonary toxicity in F344 rats exposed by inhalation to cross-linked water-soluble acrylic acid polymers

BackgroundRecently in Japan, six workers at a chemical plant that manufactures resins developed interstitial lung diseases after being involved in loading and packing cross-linked water-soluble acrylic acid polymers (CWAAPs). Since CWAAPs are not on the list of occupational diseases, the present study examined the lung damage potential of two CWAAPs (CWAAP-A and CWAAP-B) in rats, investigated pathological mechanisms, and established a method to rapidly evaluate the harmfulness of CWAAPs. MethodsUsing a whole-body inhalation exposure system, male F344 rats were exposed once to 40 or 100 mg/m3 of CWAAP-A for 4 hours or to 15 or 40 mg/m3 of CWAAP-A for 4 hours per day once per week for 2 months (a total of 9 exposures). In a separate set of experiments, male F344 rats were administered 1 mg/kg CWAAP-A or CWAAP-B by intratracheal instillation once every two weeks for 2 months (a total of five doses). Lung tissues, mediastinal lymph nodes, and bronchoalveolar lavage fluid were collected and subjected to biological and histopathological analyses. ResultsA single 4-hour exposure to CWAAP caused alveolar injury, and repeated exposures resulted in regenerative changes in the alveolar epithelium with activation of TGF{beta} signaling. During the recovery period after the last exposure, some alveolar lesions were partially healed, but other lesions developed into alveolitis with fibrous thickening of the alveolar septum. Rats administered CWAAP-A by intratracheal instillation developed qualitatively similar pulmonary pathology as rats exposed to CWAAP-A by inhalation. At 2 weeks after intratracheal instillation, rats administered CWAAP-B appeared to have a slightly higher degree of lung lesions compared to rats administered CWAAP-A, however, there was no difference in these lesions of CWAAP-A and CWAAP-B in rats examined 18 weeks after administration of these materials. ConclusionsThe present study provides evidence of rat lung pathogenesis after inhalation exposure to CWAAP-A. This study also demonstrates that the lung pathology of rats exposed to CWAAP-A by systemic inhalation was qualitatively similar to that of rats administered CWAAP-A by intratracheal instillation. The use of intratracheal instillation as an adjunct to systemic inhalation is expected to significantly accelerate the risk assessment for a variety of CWAAPs.

pharmacology and toxicology↗

bioRxiv2021

Distribution of multi-unit pitch responses recorded intracranially from human auditory cortex

The perception of pitch requires the abstraction of stimulus properties related to the spectrotemporal structure of sound. Previous studies utilizing both animal electrophysiology and human imaging have indicated the presence of a center for pitch representation in the auditory cortex. Recent data from our own group - examining local field potentials (LFPs) in humans - indicate more widely distributed pitch-associated responses within the auditory cortex (Gander et al., 2019). To probe this with greater spatial resolution, we examined multi-unit activity related to three different auditory stimuli, in seven epilepsy patients who were implanted with high-impedance electrodes in auditory cortex for the clinical purpose of localizing seizures. The stimuli were regular-interval noise (RIN) with a pitch strength that is related to the temporal regularity, and pitch value determined by repetition rate, and harmonic complexes with missing fundamentals. We demonstrated increases in spiking activity in 69 of 104 (66%) responsive multiunit activity in auditory cortex due to pitch-associated stimuli. Importantly, these responses were distributed across the entire extent of Heschls gyrus (HG), in both primary and non-primary areas, rather than isolated to a specific region, and this finding was evident regardless of the stimulus presented. These findings are the first multi-unit pitch responses recorded from humans, and align with a recent study in macaques (Kikuchi et al., 2019) demonstrating that both local field potential and unit responses to pitch-inducing stimuli are distributed throughout auditory cortex. Significance StatementThe perception of pitch is a fundamental acoustic attribute that is mediated by the auditory system. Despite its importance, there is still debate as to the precise areas responsible for its encoding, which may be due to differences in the recording measures and choices of stimuli used in previous studies. Here, we present the first study to measure multi-unit pitch responses in the auditory cortices of intracranially-implanted humans. Importantly, we demonstrate reliable responses to three different pitch-inducing paradigms that are distributed throughout Heschls gyrus, rather than being localized to a particular region. These data provide a bridge across animal and human studies, and aid in our understanding of the processing of a critical attribute of acoustic stimuli.

neuroscience↗

bioRxiv2021

Identification of transcription termination defects at DNA hypomethylated transcription termination sites in DNA methyltransferase 3a-deficient vertebrates.

CpG methylation in genomic DNA is well known as a repressive epigenetic marker in eukaryotic transcription, and DNA methylation of the promoter regions is correlated with silencing of gene expression. In contrast to the promoter regions, the function of DNA methylation during transcription termination remains to be elucidated. A recent study has revealed that mouse DNA methyltransferase 3a (Dnmt3a) mainly functions in de novo methylation in the promoter and gene body regions (including transcription termination sites (TTSs)) during development. To investigate the relationship between DNA methylation overlapping the TTSs and transcription termination, we employed two strategies: informatic analysis using already deposited datasets of Dnmt3a-/- mouse cells and the zebrafish model system. Bioinformatic analysis using methylome and transcriptome data showed that hypomethylated differentially methylated regions overlapping the TTSs were associated with increased read counts and chimeric transcripts downstream of TTSs in Dnmt3a-/- Agouti-related protein neurons, but not in Dnmt3a-/- embryonic stem cells and mouse embryonic fibroblasts. We experimentally detected increased read-through and chimeric transcripts downstream of hypomethylated TTSs in zebrafish maternal-zygotic dnmt3aa-/- mutant. This study is the first to identify transcription termination defects in DNA hypomethylated TTSs in Dnmt3a-/- vertebrates.

genomics↗

bioRxiv2020

Odor mixture perception: can molecular complexity be a factor determining elemental or configural perception?

Odor mixtures can evoke smells that differ from those of their individual odor components. Research has revealed the existence of two perceptual modes, in which a mixture can be perceived as either the original smells of its individual components (elemental) or as a novel smell (configural). However, the factors underlying the perceptual transformation that occurs when smelling a mixture versus its original components remain unclear. Therefore, the present study aimed to identify the properties of odorants that affect olfactory perception of odor mixtures, focusing on the structural complexity of an odorant. We conducted psychophysical experiments in which different groups of participants were instructed to provide olfactory perceptual descriptions of low-, medium-, and high-complexity odor mixtures or components, respectively. To investigate the perceptual modes induced by the mixtures, we compared the participants evaluations between mixtures and components via two types of analyses. First, we compared each olfactory description following quantification via principal component analysis. We then compared data based on seven major olfactory perceptual groups. We observed that odor mixtures composed of low-complexity odorants were perceived as relatively novel smells with regard to both minor (olfactory descriptions) and major (perceptual community) odor qualities than medium- and high-complexity mixtures. Such information may further our understanding of the olfactory perceptual modes of odor mixtures.

neuroscience↗

bioRxiv2020

Common Fronto-temporal Effective Connectivity in Humans and Monkeys

Cognitive pathways supporting human language and declarative memory are thought to have uniquely evolutionarily differentiated in our species. However, cross-species comparisons are missing on site-specific effective connectivity between regions important for cognition. We harnessed a new approach using functional imaging to visualize the impact of direct electrical brain stimulation in human neurosurgery patients. Applying the same approach with macaque monkeys, we found remarkably comparable patterns of effective connectivity between auditory cortex and ventro-lateral prefrontal cortex (vlPFC) and parahippocampal cortex in both species. Moreover, in humans electrical tractography revealed rapid evoked potentials in vlPFC from stimulating auditory cortex and speech sounds drove vlPFC, consistent with prior evidence in monkeys of direct projections from auditory cortex to vocalization responsive regions in vlPFC. The results identify a common effective connectivity signature that from auditory cortex is equally direct to vlPFC and indirect to the hippocampus (via parahippocampal cortex) in human and nonhuman primates. HighlightsO_LIPrivileged human auditory to inferior frontal connectivity, linked to monkeys C_LIO_LICommon auditory to parahippocampal effective connectivity in both species C_LIO_LIGreater lateralization in human effective connectivity, more symmetrical in monkeys C_LIO_LIHuman fronto-temporal network function rooted in evolutionarily conserved signature C_LI eTOC short summaryFunctional connectivity between regions crucial for language and declarative memory is thought to have substantially differentiated in humans. Using a new technique to similarly visualize directional effective connectivity in humans and monkeys, we found remarkably comparable connectivity patterns in both species between fronto-temporal regions crucial for cognition.

neuroscience↗

bioRxiv2019

Neuropeptide B mediates female sexual receptivity in medaka fish, acting in a female-specific but reversible manner

Male and female animals display innate sex-specific mating behaviors. Among vertebrates, teleosts are unique in that altering the adult sex steroid milieu can reverse sex-typical mating behaviors, suggesting sexual lability of their brains. In the teleost medaka, neuropeptide B (NPB) is expressed female-specifically in the brain nuclei implicated in mating behavior. Here, we demonstrate that NPB is a direct mediator of estrogen action on female mating behavior, acting in a female-specific but reversible manner. Analysis of regulatory mechanisms revealed that the female-specific expression of NPB is dependent on direct transcriptional activation by estrogen via an estrogen-responsive element and is reversed in response to changes in the adult sex steroid milieu. Behavioral studies of NPB knockouts revealed that female-specific NBP mediates female receptivity to male courtship. The female-specific NPB signaling identified herein is presumably a critical element of the neural circuitry underlying sexual dimorphism and lability of mating behaviors in teleosts.

neuroscience↗

bioRxiv2019

Higher seroprevalence of Entamoeba histolytica than that of HIV-1 at a voluntary counselling and testing centre in Tokyo

BackgroundAmebiasis, which is caused by Entamoeba histolytica, is a re-emerging public health issue owing to sexually transmitted infection (STI) in Japan. However, epidemiological data are quite limited. MethodologyTo reveal the relative prevalence of sexually transmitted E. histolytica infection to other STIs, we conducted a cross-sectional study at a voluntary counselling and testing (VCT) centre in Tokyo. Seroprevalence of E. histolytica was assessed according to positivity with an enzyme-linked immunosorbent assay for E. histolytica-specific IgG in serum samples collected from anonymous VCT clients. Principal FindingsAmong 2,083 samples, seropositivity for E. histolytica was 2.64%, which was higher than that for HIV-1 (0.34%, p < 0.001) and comparable to that for syphilis (rapid plasma reagin (RPR) 2.11%, p = 0.31). Positivity for Chlamydia trachomatis in urine by transcription-mediated amplification (TMA) was 4.59%. Seropositivity for E. histolytica was high among RPR-or Treponema pallidum hemagglutination (TPHA)-positive individuals and it was not different between clients with and without other STIs. Both seropositivity of E. histolytica and RPR were high among male clients. The seropositive rate for anti-E. histolytica antibody was positively correlated with age. TMA positivity for urine C. trachomatis was high among female clients and negatively correlated with age. Regression analysis identified that male sex, older age, and TPHA-positive results are independent risk factors of E. histolytica seropositivity. ConclusionsSeroprevalence of E. histolytica was 7.9 times higher than that of HIV-1 at a VCT centre in Tokyo, with a tendency to be higher among people at risk for syphilis infection. Author summaryAmebiasis caused by Entamoeba histolytica is an increasingly prevalent sexually transmitted infection (STI) in Japan; however, relative to other STIs, the prevalence of E. histolytica has not been fully assessed. We investigated the seropositivity of E. histolytica using serum samples from 2,083 clients of a voluntary counselling and testing centre in Tokyo. E. histolytica seroprevalence (2.64%) was 7.9 times higher than that of HIV-1 (0.31%) and the same as that of syphilis (rapid plasma reagin: 2.11%). Logistic regression analysis showed that E. histolytica seroprevalence tended to be higher among individuals who were male, older, and positive in Treponema pallidum hemagglutination. These results strongly suggest that public health interventions should be considered to control sexual transmission of E. histolytica infection, which is currently neglected in Japan.

microbiology↗

bioRxiv2018

Extreme genetic signatures of local adaptation during plant colonization

Colonization of new habitats is expected to require genetic adaptations to overcome environmental challenges. Here we use full genome re-sequencing and extensive common garden experiments to investigate demographic and selective processes associated with the recent colonization of Japan by Lotus japonicus. We carefully track the colonization process where L. japonicus gradually spread from subtropical conditions to much colder climates in northern Japan. We characterize the loss of diversity during this process and identify genomic regions with extreme genetic differentiation. Next, we perform population structure-corrected association mapping of phenotypic traits measured in a common garden and discover a number of genome-wide significant associations. Contrasting these analyses, we find that there is a strong concordance between phenotypic variation and extreme differentiation for overwintering and flowering time traits. Our results provide evidence that these traits were direct targets of selection by local adaptation during the colonization process and point to associated candidate genes.

evolutionary biology↗

bioRxiv2018

Microinjection into the Caenorhabditis elegans embryo using an uncoated glass needle enables cell lineage visualization and reveals cell-non-autonomous adhesion control

Microinjection is a useful method in cell biology, with which exogenous substances are introduced into a cell in a location- and time-specific manner. The Caenorhabditis elegans embryo is an important model system for cell and developmental biology. Applying microinjection to the C. elegans embryo had been difficult due to the rigid eggshell surrounding the embryo. In 2013, microinjection method using a carbon-coated quartz needle for the C. elegans embryo was reported. To prepare the needle, unfortunately, special equipment is required and thus a limited number of researchers can use this method. In this study, we established a method for the microinjection of drugs, dyes, and microbeads into the C. elegans embryo using an uncoated glass needle that can be produced in a general laboratory. This method enabled us to easily detect cell lineage up to adult stages by injecting a fluorescent dye into a blastomere. We also found a cell-non-autonomous control mechanism of cell adhesion; specifically, the injection of an actin inhibitor into one cell at the 2-cell stage enhanced adhesion between daughter cells of the other cell. Our microinjection method is expected to be used for broad studies and could facilitate various discoveries using C. elegans.

cell biology↗

bioRxiv2017

Galectin-3 and N-acetylglucosamine promote myogenesis and improve skeletal muscle function in the mdx model of Duchenne muscular dystrophy

The muscle membrane, sarcolemma, must be firmly attached to the basal lamina. The failure of proper attachment results in muscle injury, which is the underlying cause of Duchenne muscular dystrophy (DMD), where mutations in the dystrophin gene disrupts the firm adhesion. In DMD patients, even moderate contraction causes damage, leading to progressive muscle degeneration. The damaged muscles are repaired through myogenesis. Consequently, myogenesis is highly active in DMD patients, and the repeated activation of myogenesis leads to the exhaustion of the myogenic stem cells. Therefore, approaches to reducing the risk of the exhaustion are to develop a treatment that strengthens the interaction between the sarcolemma and the basal lamina, and increases the efficiency of myogenesis. Galectin-3 is an oligosaccharide-binding protein and known to be involved in cell-cell interactions and cell-matrix interactions. Galectin-3 is expressed in myoblasts and skeletal muscle while its function in muscle remains elusive. In this study, we found evidence that galectin-3 and the monosaccharide N-acetylglucosamine, which increases the ligands (oligosaccharides) of galectin-3, promotes myogenesis in vitro. Moreover, in the mdx mouse model of DMD, treatment with N-acetylglucosamine increased the muscle force production. Our results demonstrate that treatment with N-acetylglucosamine can mitigate the burden of DMD.

pathology↗