Biology subjects

Lark, D.

Publications and source records attributed to Lark, D..

3 recordsLinked to original sources

bioRxiv2025

Alpha Parvin Promotes Glucose Uptake and Metabolism in Skeletal Muscle with Minimal Influence on Hepatic Insulin Sensitivity

Skeletal muscle and liver insulin resistance are early features in the sequelae of type 2 diabetes. Integrins are extracellular matrix receptors expressed on skeletal muscle cells and hepatocytes and have been implicated in modulating obesity-associated insulin resistance. Integrins regulate cell function through intracellular proteins including the ILK-PINCH-Parvin (IPP) complex. ILK promotes skeletal muscle and liver insulin resistance in diet-induced obesity in mice but the role of Parvin is unexplored. Here we demonstrate that hepatocyte specific deletion of -Parvin had only minimal influence on endogenous glucose production or whole-body insulin sensitivity. In contrast, deletion of -Parvin in skeletal muscle caused a striking reduction in muscle glucose uptake during an insulin clamp in lean mice which was not exacerbated by diet-induced obesity. Insulin-mediated GLUT4 membrane recruitment was impaired in mutant muscles which displayed significant morphological abnormalities due to actin cytoskeleton dysfunction. Consistent with severe muscular dysfunction, mitochondrial oxidative capacity and aerobic exercise capacity were blunted in muscle -Parvin-null mice. Thus, -Parvin has a minor role in liver insulin action but is required for insulin-stimulated glucose uptake in skeletal muscle due to its role in actin cytoskeleton regulation. These data suggest that individual IPP complex proteins link cell structure to metabolism via distinct mechanisms in a tissue-specific fashion.

physiology↗

bioRxiv2024

Predicting cell type-specific extracellular vesicle biology using an organism-wide single cell transcriptomic atlas - insights from the Tabula Muris

Extracellular vesicles (EVs) like exosomes are functional nanoparticles trafficked between cells and found in every biofluid. An incomplete understanding of which cells, from which tissues, are trafficking EVs in vivo has limited our ability to use EVs as biomarkers and therapeutics. However, recent discoveries have linked EV secretion to expression of genes and proteins responsible for EV biogenesis and found as cargo, which suggests that emerging "cell atlas" datasets could be used to begin understanding EV biology at the level of the organism and possibly in rare cell populations. To explore this possibility, here we analyzed 67 genes that are directly implicated in EV biogenesis and secretion, or carried as cargo, in [~]44,000 cells obtained from 117 cell populations of the Tabula Muris. We found that the most abundant proteins found as EV cargo (tetraspanins and syndecans) were also the most abundant EV genes expressed across all cell populations, but the expression of these genes varied greatly among cell populations. Expression variance analysis also identified dynamic and constitutively expressed genes with implications for EV secretion. Finally, we used EV gene co-expression analysis to define cell population-specific transcriptional networks. Our analysis is the first, to our knowledge, to predict tissue- and cell type-specific EV biology at the level of the organism and in rare cell populations. As such, we expect this resource to be the first of many valuable tools for predicting the endogenous impact of specific cell populations on EV function in health and disease.

cell biology↗

bioRxiv2020

Skeletal muscle tissue secretes more extracellular vesicles than white adipose tissue and myofibers are a major source ex vivo but not in vivo.

Circulating extracellular vesicles (EVs) are biomarkers of and contributors to the etiology of disease. Skeletal muscle (SkM) and white adipose tissue (WAT) are the two largest organs by mass in humans and rodents but the relative contribution of EVs from these tissues is unknown. We hypothesized that SkM tissue secretes more EVs than WAT and that a dual fluorescent reporter mouse could be used to detect SkM myofiber-derived EVs in vivo. Human Protein Atlas data and directly measuring EV secretion in mouse SkM and WAT using an ex vivo tissue explant model confirmed that SkM tissue secretes more EVs than WAT. Differences in EV secretion between SkM and WAT were not due to SkM contraction but may be explained by differences in tissue metabolic capacity. A SkM myofiber-specific dual fluorescent reporter mouse was created. Spectral flow cytometry revealed that SkM myofibers are a major source of SkM tissue-derived EVs ex vivo but few reach the circulation in vivo. Our findings demonstrate that SkM secretes more EVs than WAT and many come from SkM myofibers, but our in vivo data indicate that EVs secreted by SkM myofibers may remain primarily in their local extracellular environment.

physiology↗