Paget, D. | bioRxiv Science

bioRxiv2024

miR-29a-3p, a new myokine orchestrating resistance exercise via coordinated metabolic responses

It remains unclear whether the adaptive response to different exercise models is mediated by EV miRNAs released from skeletal muscle and their functional metabolic role. We sequenced miRNA-loaded plasma EVs obtained from resting mice after 4-weeks endurance or resistance training. Resistance exercise increased the expression of a 11-miRNA profile grouped into two functional clusters. Using both genetically modified animal models and in vitro approaches, we have identified miR-29a-3p as a novel myokine secreted into the bloodstream as EV cargo by contracting skeletal muscle. It is a cornerstone in the adaptation to resistance training by mediating the coordinated expression and secretion of other miRNAs and affecting muscle mass development and energy metabolism in muscle and liver. Taken together, our study suggests a coordinating and determinant role of miR-29a-3p in the response and adaptation to resistance training, possibly due to its role as a myokine through its regulatory role in energy metabolism.

molecular biology↗

bioRxiv2023

Multi-organ single-cell RNA-sequencing reveals early hyperglycaemia responses that converge on fibroblast dysregulation

Diabetes causes a range of complications that can affect multiple organs. Hyperglycaemia is an important driver of diabetes-associated complications, mediated by biological processes such as dysfunction of endothelial cells, fibrosis and alterations in leukocyte number and function. Here, we dissected the transcriptional response of key cell types to hyperglycaemia across multiple tissues using single-cell RNA-seq (scRNA-seq) and identified conserved, as well as organ-specific, changes associated with diabetes complications. By studying an early timepoint of diabetes, we focus on biological processes involved in the initiation of the disease, before the later organ-specific manifestations had supervened. We used a mouse model of type 1 diabetes and performed scRNA-seq on cells isolated from the heart, kidney, liver and spleen of streptozotocin-treated and control mice after 8 weeks and assessed differences in cell abundance, gene expression, pathway activation and cell signalling across organs and within organs. In response to hyperglycaemia, endothelial cells, macrophages and monocytes displayed organ-specific transcriptional responses, whereas fibroblasts showed similar responses across organs, exhibiting a myofibroblast-like phenotype with altered metabolic gene expression and increased differentiation of myeloid-derived fibroblasts. Further, we found evidence of endothelial dysfunction in the kidney, and of endothelial to mesenchymal transition in streptozotocin-treated mouse organs. In summary, our study represents the first single-cell and multi-organ analysis of early dysfunction in type 1 diabetes-associated hyperglycaemia, and our large-scale dataset (comprising 67,611 cells) will serve as a starting point, reference atlas, and resource for further investigating the events leading to early diabetic disease.

cell biology↗