Biology subjects

McKay, M.

Publications and source records attributed to McKay, M..

4 recordsLinked to original sources

bioRxiv2026

Short-term dietary change rapidly remodels microbial community assemblages and reprogrammed systemic immune phenotypes

Diet is a major determinant of the gut microbiome and immune homeostasis, yet the extent to which short-term dietary interventions can remodel established microbial communities and reprogramme immune phenotypes following long-term western diet consumption remains poorly understood. Here, we investigated temporal dynamics of the gut microbiome, microbial metabolites, intestinal barrier function and local and systemic immune responses following diet switching. Mice were fed either a standard chow or a western diet for 8 weeks before remaining on these diets or switching to the alternate diet for 2 or 4 weeks. Long term consumption of chow and western diets resulted in distinct gut microbial communities and differences in intestinal permeability. Diet switching rapidly remodelled microbial community structure within two weeks, with substantial bidirectional changes in community composition. Despite these changes, the relative abundance of several taxa remained influenced by prior dietary exposure. In contrast, faecal SCFA profiles remained largely associated with long-term diet, indicating that microbial metabolic outputs were altered more slowly than microbial community composition. Mass cytometry revealed progressive remodelling of local (MLN) and systemic (PBMC and spleen) immune responses following dietary switching. Activation-associated immune phenotypes, including Ki67+ and PD-1+ B and T cells, inflammatory monocytes and ROR{gamma}t+ regulatory T cells, rapidly responded to diet switching, whereas overall B cells, regulatory T cells and effector memory T cells retained signatures of long-term dietary exposure. Together, these findings demonstrate distinct temporal dynamics across the diet-microbiome-immune axis, whereby gut microbial composition and immune activation states remain highly plastic, while microbial metabolic outputs and several memory and regulatory immune phenotypes exhibit persistent dietary imprinting. These findings highlight the potential utility of short-term dietary interventions to modulate host-microbiome interactions and immune homeostasis.

immunology↗

bioRxiv2025

FGF13 regulates cardiomyocyte impulse propagation via Cx43 trafficking independent of voltage-gated sodium channels

BackgroundFibroblast growth factor homologous factor (FHF) variants associate with arrhythmias. Although FHFs are best characterized as regulators of voltage gated sodium channel (VGSC) gating, recent studies suggest broader, non-VGSC-related functions, including regulation of Cx43 gap junctions and/or hemichannels, mechanisms that have generally been understudied or disregarded. MethodsWe assessed cardiac conduction and cardiomyocyte action potentials in mice with constitutive cardiac-specific Fgf13 ablation (cFgf13KO) while targeting Cx43 gap junctions and hemichannels pharmacologically. Using immunostaining and biochemistry, we characterized FGF13 regulation of Cx43 abundance and subcellular distribution. With proximity labeling proteomics, we investigated novel candidate mechanisms underlying FGF13 regulation of Cx43. ResultsFGF13 ablation prolonged the QRS and QT intervals on the surface electrocardiogram. Carbenoxolone, a Cx43 gap junction uncoupler, markedly prolonged the QRS duration leading to conduction system block in cFgf13KO but not in WT mice. Optical mapping revealed markedly decreased conduction velocity (CV) during ventricular pacing. Microscopy revealed markedly perturbed trafficking of Cx43, reduced localization in the intercalated disc, and suggested decreased membrane Cx43 but increased Cx43 hemichannels in cardiomyocytes from cFgf13KOmice. Resting membrane potential (RMP) was depolarized and APD50 was prolonged in cFgf13KOcardiomyocytes. Both were restored towards wildtype (WT) values with Gap19 (a Cx43 hemichannel inhibitor), expression of FGF13, or expression of a mutant FGF13 incapable of binding to VGSCs, emphasizing VGSC-independent regulation by FGF13. To assess the functional impact of RMP depolarization, hearts were subjected to hypokalemia, which had no effect in WT hearts but fully rescued CV in cFgf13KO hearts. Proteomic analyses revealed candidate roles for FGF13 in the regulation of vesicular-mediated transport. Biochemistry and immunocytochemistry showed that FGF13 ablation destabilized microtubules and reduced the expression of tubulins and MAP4, the major cardiac microtubule regulator. ConclusionsFGF13 regulates microtubule-dependent trafficking and targeting of Cx43, thereby impacting cardiac impulse propagation via VGSC-independent mechanisms.

physiology↗

bioRxiv2025

Transient AMPK activation by nutrient stress of high fat diet preserves cardiac electrophysiological stability and protects against arrhythmias

Sudden cardiac death (SCD) is a major complication of obesity, yet it remains unclear whether early metabolic stress, prior to the onset of overt obesity or structural remodeling, can independently promote arrhythmias. In vitro studies suggest that fatty acids can allosterically stimulate AMP-activated protein kinase (AMPK), a key metabolic sensor known to preserve myocardial viability and mitochondrial function following ischemia-reperfusion (I/R) injury. We hypothesized that AMPK signaling critically modulates the electrophysiological (EP) response to high-fat diet (HFD)-induced metabolic stress. MethodsTo test this, wild-type (WT) and AMPK kinase-dead (AMPK-KD) mice were subjected to an 8-week HFD regimen beginning at 4 weeks of age. Controls remained on normal diet (ND) for the same duration. Arrhythmia susceptibility was assessed ex vivo using rapid pacing and I/R challenge protocols. Changes in the EP substrate were defined by high-resolution optical action potential mapping. Underlying mechanisms were probed using western blotting, confocal and transmission electron microscopy. ResultsHFD-fed wild-type (WT) hearts did not display increased arrhythmia susceptibility in response to either burst pacing or I/R challenge. On the contrary, they exhibited a paradoxical enhancement in post-ischemic EP recovery compared to ND-fed controls. This improvement was associated with increased phosphorylation of canonical AMPK targets, including acetyl-CoA carboxylase (ACC) and raptor, consistent with the activation of a cardioprotective metabolic program. In sharp contrast, AMPK-deficient (AMPK-KD) hearts demonstrated heightened vulnerability to inducible ventricular tachycardia (VT), irrespective of diet. Conduction slowing emerged as an early EP abnormality in these hearts and served as the initial substrate (or first hit) that promoted their increased incidence of non-sustained VT. Notably, this conduction impairment arose in conjunction with an increase (rather than decrease) in Cx43 and Nav1.5 protein expression. Mechanistically, defective conduction in AMPK-KD hearts was linked to impaired autophagic degradation of intercalated disc proteins resulting from reduced phosphorylation of ULK1, a downstream effector of AMPK. Consequently, unphosphorylated Cx43 accumulated at the intercalated disc, likely replacing phosphorylated isoforms (p-Cx43). In addition, AMPK-KD hearts exhibited swollen, fragmented mitochondria and reduced levels of mitochondrial fusion proteins. Upon HFD challenge, this vulnerable mitochondrial substrate generated excessive reactive oxygen species (ROS) coinciding with accelerated repolarization. Together, impaired conduction and action potential shortening promoted VT sustenance in HFD-fed AMPK-deficient hearts. ConclusionsOur findings identify AMPK as a key metabolic regulator that integrates redox balance, mitochondrial integrity, and protein homeostasis to preserve cardiac excitability during early nutrient overload. Loss of AMPK signaling, as occurs with aging and advanced metabolic disease, may therefore represent a pivotal mechanism linking HFD to increased SCD risk.

physiology↗

bioRxiv2021

SARS-CoV-2 T cell responses are expected to remain robust against Omicron

Omicron, the most recent SARS-CoV-2 variant of concern (VOC), harbours multiple mutations in the spike protein that were not observed in previous VOCs. Initial studies suggest Omicron to substantially reduce the neutralizing capability of antibodies induced from vaccines and previous infection. However, its effect on T cell responses remains to be determined. Here, we assess the effect of Omicron mutations on known T cell epitopes and report data suggesting T cell responses to remain broadly robust against this new variant.

immunology↗