Manuel, A. | Search bioRxiv

bioRxiv2024

Semaglutide-induced weight loss improves mitochondrial energy efficiency in skeletal muscle

ObjectiveGlucagon-like peptide 1 receptor agonists (e.g. semaglutide) potently induce weight loss and thereby reducing obesity-related complications. However, weight regain occurs when treatment is discontinued. An increase in skeletal muscle oxidative phosphorylation (OXPHOS) efficiency upon diet-mediated weight loss has been described, which may contribute to reduced systemic energy expenditure and weight regain. We set out to determine the unknown effect of semaglutide on muscle OXPHOS efficiency. MethodsC57BL/6J mice were fed a high-fat diet for 12 weeks before receiving semaglutide or vehicle for 1 or 3 weeks. The rate of ATP production and O2 consumption were measured by a high-resolution respirometry and fluorometry to determine OXPHOS efficiency in skeletal muscle at these 2 timepoints. ResultsSemaglutide treatment led to significant reductions in fat and lean mass. Semaglutide improved skeletal muscle OXPHOS efficiency, measured as ATP produced per O2 consumed (P/O) in permeabilized muscle fibers. Mitochondrial proteomic analysis revealed changes restricted to two proteins linked to complex III assembly (Lyrm7 and Ttc1, p <0.05 without multiple corrections) without substantial changes in the abundance of OXPHOS subunits. ConclusionsThese data indicate that weight loss with semaglutide treatment increases skeletal muscle mitochondrial efficiency. Future studies could test whether it contributes to weight regain.

physiology↗

bioRxiv2022

A single-cell atlas of the human brain in Alzheimer's disease and its implications for personalized drug repositioning

Alzheimers disease (AD) is a neurodegenerative disease with complex pathophysiology, and AD-dysregulated pathways are inconsistent across different brain regions and patients. Although single-cell RNA sequencing (scRNA-seq) has been performed in different regions of postmortem AD brains, the common and distinct molecular features among different regions remains largely unclear. This hinders the discovery of repurposable and personalized drugs for AD. We combined four scRNA-seq datasets and systematically investigated the common and distinct cellular responses, cell subpopulations, and transcription factors involved in AD. Moreover, we explored the transcriptional heterogeneity of different AD subtypes at the single-cell level. Finally, we conducted individual-based drug repurposing analysis to explore repurposable and personalized drugs. Six major brain cell types were detected after scRNA-seq batch-effect removal and noise cells filtering. Integration with genome-wide association studies (GWAS) summary statistics demonstrated that AD-susceptible genes were mainly enriched with differentially expressed genes (DEGs) in glial cells rather than neuronal cells. While most of DEGs were regulated in opposite directions among different cell types, cell-cell communication analysis revealed several common cellular interaction events involved in neurogenesis, as well as increased cell-cell adhesion. Our comprehensive drug repositioning analysis identified new candidates for AD treatment, including trichostatin, which was predicted to be broadly applicable to different identified AD subtypes, and vorinostat, which was specific for one subtype of AD. In summary, we delineated a cell-specific atlas of the AD transcriptome. Our work illustrated strong cellular heterogeneity in AD for defining AD subtypes. The cell-specific features are important for understanding AD etiology, progression, and drug discovery.

bioinformatics↗