SMILED · Skeletal Muscle Inflammation: ambivalent roles in Exercise and Diabetes

Skeletal Muscle Inflammation: ambivalent roles in Exercise and Diabetes

In Europe, 52 million people are living with diabetes and the world health organization estimates that it will be the 7th leading cause of death worldwide by 2030. Diabetes leads to severe complications such as cardiovascular events and certain forms of cancers and therefore constitutes an economic burden of unmanageable proportions. More than 90% of diabetic patients have type 2 diabetes (T2D), a complex multifactorial disease typically associated with obesity and sedentary lifestyle. Skeletal muscle is the major site of dietary glucose disposal and therefore a key player in the development of whole-body insulin resistance, the first step toward to the development of T2D. T2D is associated with chronic low-grade inflammation and muscle inflammation is emerging as a potential contributor to insulin resistance. Recent reports show that inflammatory immune cell numbers within muscle are elevated during obesity and I and others have demonstrated that muscle cells in vitro can mount inflammatory responses under metabolic challenges. The overall aim of this proposal was to determine the interaction between inflammation and the metabolic response to exercise and T2D. • Aim 1: Characterize and compare muscle inflammation in humans during exercise and T2D. Identify pathways specific to muscle which could be targetable to improve insulin sensitivity. • Aim 2: Develop strategies to emulate diabetes and exercise in vitro and modulate inflammatory responses in order to improve insulin sensitivity or alleviate insulin resistance. • Aim 3: Determine if and how skeletal muscle cells retain a memory of exercise or diabetes in vitro through epigenetic modifications and how this impacts on inflammation and insulin resistance. Using biopsies, primary cells and publically available data, we characterized the gene response of human skeletal muscle to exercise and type 2 diabetes. A meta-analysis of 63 published exercise studies was performed and the database made public at www.metamex.eu. The statistical power from this approach allowed us to clearly separate the skeletal muscle response to acute versus chronic exercise training. Bioinformatics analyses revealed selective pathways activated by inactivity and various exercise types. This meta-analysis also shed light on the adverse response to exercise in metabolically impaired individuals. In parallel, we recruited type 2 diabetic volunteers who performed a single bout of aerobic exercise in the lab. We analyzed biopsies and plasma before and after the exercise and discovered that type 2 diabetic individuals had a selective inflammatory response not observed in control volunteers. The identification of this specific response has the potential to lead to specific inflammatory-based interventions to improve the response to exercise and metabolic parameters in metabolically impaired individuals. In vitro, we developed models of “exercise in a dish” by contracting muscle with electrical pulse stimulation and models of “diabetes in a dish” by exposing cells to high levels of sugar or fat. These models allowed us to validate the data observed in human biopsies and more precisely define the molecular pathways involved. We discovered that cells grown in diabetes-like conditions or cells grown from type 2 diabetic individuals had an altered response to contraction, especially on inflammatory genes. Overall, the data obtained during this MSCA fellowship expanded our understanding of the gene response of skeletal muscle to exercise and diabetes. We developed novel approaches like MetaMEx and advanced technologies and bioinformatics to identify novel targets. Many of these are currently under thorough examination for their potential as pharmacological interventions to enhance the benefits of exercise and improve metabolic health.

Data: CORDIS, © European Union