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UNDERSTANDING THE METABOLIC CROSSTALK BETWEEN THE MUSCLE AND THE ENDOTHELIUM: IMPLICATIONS FOR EXERCISE TRAINING AND INSULIN RESISTANCE

Periodic Reporting for period 2 - MusEC (UNDERSTANDING THE METABOLIC CROSSTALK BETWEEN THE MUSCLE AND THE ENDOTHELIUM: IMPLICATIONS FOR EXERCISE TRAINING AND INSULIN RESISTANCE)

Reporting period: 2018-12-01 to 2020-05-31

Obesity has become a leading medical disorder, which is associated with life threatening conditions such as glucose intolerance, insulin resistance (IR) and type 2 diabetes (T2D). In the maintenance of glucose homeostasis, muscle is a critical organ and current health recommendations include regular physical activity as a cornerstone in the prevention and treatment of IR/T2D. The development of therapeutics that mimick the health promoting effects of exercise (so-called exercise mimetics) has been proposed as a novel strategy. However, this has been proven difficult, because we still do not completely understand how exercise improves glucose tolerance. In particular, angiogenesis – the growth of new blood vessels from existing ones – is an early adaptive event following exercise training, but the role of the muscle vasculature in the regulation of muscle metabolism and glucose tolerance has been largely overlooked.
In this project, my lab investigates the metabolic crosstalk between the vasculature and the muscle to increase our understanding on how the endothelium interacts with the muscle and how endothelial cells contribute to muscle metabolism and glucose homeostasis. First, we are studying whether and how vessels need to reprogram their metabolism to promote angiogenesis following exercise training. Second, we are exploring whether this metabolic reprogramming is required for the muscle to allow training adaptations. We also hypothesize that endothelial cells and the muscle intensely communicate to ensure optimal muscle function and to orchestrate muscle adaptations to exercise training via metabolic signaling. Ultimately, we will investigate whether this communication is affected during the development of T2D and if so, whether this interaction can be exploited to prevent IR/T2D.
We have identified that the muscle contains different kinds of capillary endothelial cells, with different metabolic characteristics and a different capacity for blood vessel formation. Interestingly, the endothelial cells with high angiogenic capacity lie close to slow muscle fibers (which are activated during low intensive movements or endurance exercise). In response to exercise, only those endothelial cells become activated and form new vessels. Currently, we are trying to understand the mechanisms behind the differences in angiogenic capacity.
We also found that endothelial cells communicate with the muscle via several ways. First, we found that endothelial cells release metabolic factors which define the function of specific immune cells (so called macrophages) in the muscle. Interestingly, the ability for endothelial cells to control the function of macrophages might offer opportunities for treating T2D patients. Indeed, those patients often develop ‘peripheral artery disease’, whereby the muscle gets hypoxic due to limited blood supply in the leg. Improving revascularization of this hypoxic leg is crucial because otherwise the leg might need to be amputated. We are currently testing whether we can improve revascularization of the hypoxic muscle by altering endothelial metabolism, and the way endothelial cells communicate with macrophages. Second, we also found that endothelial cells can directly control muscle insulin sensitivity through the release of specific signal peptides. While we have clearly showed this in cells, we are now developing mouse models where we can further test this.
In another subproject, we noticed that inhibiting endothelial fat oxidation prevents mice from becoming obese. However, this was not because of alterations in muscle metabolism, and we are currently trying to understand how endothelial cells can control whole body metabolism. These exciting findings show that the role of the vasculature goes far beyond delivering oxygen and nutrients to tissues.
The growth of new blood vessels is crucial for the success of regenerative therapies for many diseases. While our knowledge about developmental angiogenesis and pathological angiogenesis has been increasing steadily, very little is known on how blood vessels grow under physiological circumstances, such as in the muscle upon exercise. By trying to understand how exercise promotes angiogenesis and how endothelial cells metabolically reprogram during exercise, we hope to identify novel mechanisms that will allow us to steer active blood vessel growth. The unique position of my lab at the crossroads of the angiogenesis field, metabolism field, exercise and muscle biology fields, will allow us to generate unprecedented insight into:
-how new blood vessels are formed in response to exercise training.
-how endothelial cells communicate with muscle to control muscle insulin sensitivity
-how endothelial metabolism can impact on whole body metabolism.
-how endothelial cells can contribute to muscle homeostasis, and control the regeneration of the muscle when it gets damaged.