Skeletal muscle is an active secretory organ. We are working on the role of extracellular vesicles (EVs) as secreting factors from skeletal muscle, what the EVs contain, and whether they can affect neighboring and distant cells.
Extracellular vesicles (EVs) are small nano-sized particles filled with bioactive molecules such as lipids, proteins, and nucleic acids.
We have found that human skeletal muscle cells secrete EVs, and that the content of the EVs reflects the current state of the muscle cells.
There are two main aims of the project.
First, to study how exercise affects EV content, and whether EVs derived from exercised skeletal muscle cells can spread the beneficial effect of exercise to target cells.
Second, to study how type 2 diabetes affects the EV content, and whether EVs from diabetic muscle cells can transmit insulin resistance to target cells.
More about the project
Skeletal muscle derived EVs as exercise factors
It is well known that physical activity has a beneficial effect on health by lowering the risk for non-communicable diseases, such as cardiovascular diseases, diabetes, certain forms of cancer and symptoms of depression.
The physiological effects of physical exercise on such different conditions imply that muscles can communicate with distant organs, and it has been shown that muscle cells secrete signaling particles called extracellular vesicles (EVs).
EVs are derived from cellular membranes and are packed with biologically active cargo including nucleic acids, proteins, and lipids that reflect the state of the host cell. Secreted by cells into extracellular space, EVs have the unique ability to communicate with other cells, neighbouring or distant, altering the recipient cell’s phenotype.
Little is known about EVs released from skeletal muscles during exercise and how they communicate both with neighbouring muscle cells and with other cell types located at distant sites.
This project aims to provide new knowledge about EVs released from skeletal muscles during exercise. Both the cargo of EVs and how they communicate with other cells will be studied.
The project is highly relevant to society as the burden of non-communicable diseases is increasing. The search for exercise factors that can contribute to the development of an “exercise pill” that provides the beneficial effects of exercise and possibly reverses the negative burden of non-communicable diseases is highly desired.
Research questions and methodology
The primary objective of the project is to explore how skeletal muscle communicates the effects of exercise through extracellular vesicles.
We have recently shown that electrical pulse stimulation (EPS - an in vitro model of physical activity) changes the EV cargo significantly. Proteomic and transcriptomic analysis revealed several interesting changes in both protein and microRNA content after EPS.
We found changes in appetite regulating factors, implying a role for physical activity in improving appetite regulation.
We will further characterize EVs derived from exercising muscle, to evaluate the metabolite content and whether these muscle-derived EVs can communicate the beneficial effects of exercise to target cells, such as insulin-resistant muscle cells and hepatocytes.
Skeletal muscle cells, isolated from human biopsies, will be grown, stimulated with different EPS protocols, and EVs will be isolated from the cell culture media. The total metabolite content of EVs will be analysed by metabolomics.
Further, EVs from EPS treated muscle cells will be added to insulin resistant muscle cells and cultured hepatocytes to see whether insulin sensitivity and energy metabolism can be improved.
EVs from insulin-resistant skeletal muscle cells
Type 2 diabetes is characterized by reduced insulin secretion from the pancreas and peripheral insulin resistance, involving adipose tissue, liver, and skeletal muscle to different degrees.
Type 2 diabetes is a heterogeneous condition with substantial variation in clinical presentations. It is usually not known to what extent the function of different metabolic organs is affected in each individual patient, i.e., pancreatic, hepatic, adipose or skeletal muscle function.
Insulin resistance of skeletal muscle contributes significantly to type 2 diabetes, as skeletal muscle is the largest insulin-sensitive organ in the body. This project aims to characterize how type 2 diabetes affects the content of skeletal muscle derived EVs.
It is possible that skeletal muscle derived EVs might function as biomarkers of insulin-resistant muscles and, thereby, contribute to understanding diabetes heterogeneity and improving precision medicine.
Whether skeletal muscle derived EVs can communicate with target cells and possibly spread the insulin resistance between organs is also important for understanding the development of type 2 diabetes.
Research questions and methodology
The primary aim of this project is to explore the role of skeletal muscle derived EVs in type 2 diabetes, both as biomarkers and in disease development.
We have isolated EVs from skeletal muscle cells from donors with normal glucose tolerance and from donors with type 2 diabetes, and characterized the protein and microRNA content.
To get a comprehensive view of the EV content, we will supplement the existing data with metabolomic analysis and look for the diabetic EV fingerprint.
Further, we will expose healthy cells to diabetic EVs and study phenotypic changes.