Biology subjects

Benvie, A. M.

Publications and source records attributed to Benvie, A. M..

3 recordsLinked to original sources

bioRxiv2024

Suppressing PDGFRβ Signaling Enhances Myocyte Fusion to Promote Skeletal Muscle Regeneration

Muscle cell fusion is critical for forming and maintaining multinucleated myotubes during skeletal muscle development and regeneration. However, the molecular mechanisms directing cell-cell fusion are not fully understood. Here, we identify platelet-derived growth factor receptor beta (PDGFR{beta}) signaling as a key modulator of myocyte fusion in adult muscle cells. Our findings demonstrate that genetic deletion of Pdgfr{beta} enhances muscle regeneration and increases myofiber size, whereas PDGFR{beta} activation impairs muscle repair. Inhibition of PDGFR{beta} activity promotes myonuclear accretion in both mouse and human myotubes, whereas PDGFR{beta} activation stalls myotube development by preventing cell spreading to limit fusion potential. Transcriptomics analysis show that PDGFR{beta} signaling cooperates with TGF{beta} signaling to direct myocyte size and fusion. Mechanistically, PDGFR{beta} signaling requires STAT1 activation, and blocking STAT1 phosphorylation enhances myofiber repair and size during regeneration. Collectively, PDGFR{beta} signaling acts as a regenerative checkpoint and represents a potential clinical target to rapidly boost skeletal muscle repair.

developmental biology↗

bioRxiv2024

Reversing Pdgfrβ Signaling Restores Metabolically Active Beige Adipocytes by Alleviating ILC2 Suppression in Aged and Obese Mice

ObjectivePlatelet Derived Growth Factor Receptor Beta (Pdgfr{beta}) suppresses the formation of cold temperature-induced beige adipocytes in aged mammals. We aimed to determine if deleting Pdgfr{beta} in aged mice could rejuvenate metabolically active beige adipocytes by activating group 2 innate lymphoid cells (ILC2), and whether this effect could counteract diet-induced obesity-associated beige fat decline. MethodsWe employed Pdgfr{beta} gain-of-function and loss-of-function mouse models targeting beige adipocyte progenitor cells (APCs). Our approach included cold exposure, metabolic cage analysis, and age and diet-induced obesity models to examine beige fat development and metabolic function under varied Pdgfr{beta} activity. ResultsAcute cold exposure alone enhanced metabolic benefits in aged mice, irrespective of beige fat generation. However, Pdgfr{beta} deletion in aged mice reestablished the formation of metabolically functional beige adipocytes, enhancing metabolism. Conversely, constitutive Pdgfr{beta} activation in young mice stymied beige fat development. Mechanistically, Pdgfr{beta} deletion upregulated IL-33, promoting ILC2 recruitment and activation, whereas Pdgfr{beta} activation reduced IL-33 levels and suppressed ILC2 activity. Notably, diet-induced obesity markedly increased Pdgfr{beta} expression and Stat1 signaling, which inhibited IL-33 induction and ILC2 activation. Genetic deletion of Pdgfr{beta} restored beige fat formation in obese mice, improving whole-body metabolism. ConclusionThis study reveals that cold temperature exposure alone can trigger metabolic activation in aged mammals. However, reversing Pdgfr{beta} signaling in aged and obese mice not only restores beige fat formation but also renews metabolic function and enhances the immunological environment of white adipose tissue (WAT). These findings highlight Pdgfr{beta} as a crucial target for therapeutic strategies aimed at combating age- and obesity-related metabolic decline.

cell biology↗

bioRxiv2022

Remodeling of gene regulatory networks underlying thermogenic stimuli-induced adipose beiging

Beige adipocytes are induced by cold temperatures or {beta}3-adrenergic receptor (Adrb3) agonists. They create heat through glucose and fatty acid (FA) oxidation, conferring metabolic benefits. The distinct and shared mechanisms by which these treatments induce beiging are unknown. Here, we performed single-nucleus assay for transposase-accessible chromatin sequencing (snATAC-seq) on adipose tissue from mice exposed to cold or an Adrb3 agonist to identify cellular and chromatin accessibility dynamics during beiging. Both stimuli induce chromatin remodeling that influence vascularization and inflammation in adipose. Beige adipocytes from cold-exposed mice have increased accessibility at genes regulating glycolytic processes, whereas Adrb3 activation increases cAMP responses. While both thermogenic stimuli increase accessibility at genes regulating thermogenesis, lipogenesis, and beige adipocyte development, the kinetics and magnitudes of the changes are distinct for the two stimuli. Accessibility changes at lipogenic genes are linked to functional changes in lipid composition of adipose. Both stimuli tend to decrease the proportion of palmitic acids, a saturated FA in adipose. However, Adrb3 activation increases the proportion of monounsaturated FAs, whereas cold increases the proportion of polyunsaturated FAs. These findings reveal common and distinct mechanisms of cold and Adrb3 induced beige adipocyte biogenesis, and identify the unique functional consequences of manipulating these pathways in vivo.

genomics↗