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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 4 - MusEC (UNDERSTANDING THE METABOLIC CROSSTALK BETWEEN THE MUSCLE AND THE ENDOTHELIUM: IMPLICATIONS FOR EXERCISE TRAINING AND INSULIN RESISTANCE)

Reporting period: 2021-12-01 to 2022-05-31

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. Moreover, since exercise-induced angiogenesis is one of the very few physiological conditions under which new (and functional) blood vessels form, studying the mechanisms underlying exercise-induced angiogenesis could be of major interest for the future development of regenerative therapies in which angiogenesis plays a crucial role.
In this project, my lab investigated 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 homeostasis.
First, we aimed at studying whether and how vessels need to reprogram their metabolism to promote angiogenesis following exercise training. We found that different muscle endothelial cell subpopulations exist. We could further show that the angiogenic response following exercise is executed by a specific EC population which is characterized by the expression of the ATF3/4 transcription factors. We found that these ATF3/4high endothelial cells are metabolically prepared for angiogenesis. In particular, ATF3/4high muscle endothelial cells control a set of genes involved in amino acid uptake and metabolism. As such, they are metabolically prepared to rapidly form new vessels under angiogenic conditions. ATF3/4- (or Atf4KD) ECs had lower amino acid uptake, and showed lower cellular amino acid levels, leading to a lower capacity for growth and vascular expansion. As a consequence, deleting atf4 in ECs impaired exercise-induced angiogenesis. We also explored whether this metabolic reprogramming is required for the muscle to allow training adaptations, but couldn't observe any impaired adaptations following short term training. In the future, we hope to harness ATF3/4high ECs to promote revascularization in regenerative settings.
We also hypothesized that endothelial cells and the muscle intensely communicate to ensure optimal muscle function and to orchestrate muscle adaptations and muscle homeostasis. We found that highly glycolytic angiogenic ECs are a main source of lactate in the muscle, particularly during muscle ischemia, and lowering angiocrine lactate production through EC-specific loss of Pfkfb3 (a main glycolytic regulator in ECs) reduced muscle revascularization and regeneration. Mechanistically, we found that EC-derived lactate drives macrophage, the main immune cell in the muscle, to acquire a pro-regenerative phenotype. This phenotype was initiated by the uptake of lactate into the macrophage (via mechanisms that we are currently investigating). Moreover, lactate shuttling by ECs enabled macrophages to promote muscle regeneration and to further stimulate angiogenesis by secreting VEGF, the main angiogenic growth factor. Thus, through the release of lactate, endothelial cells shape a pro-regenerative and pro-angiogenic environment and a such control muscle regeneration. Ultimately, we aim to 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. (Fan et al. Cell Metabolism 2021)
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 (Zhang et al., Cell Metabolism 2021). 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. In the future, we will test whether we can improve revascularization of the hypoxic muscle by altering endothelial metabolism, and the way endothelial cells communicate with macrophages.
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 identified novel mechanisms that will allow us to develop strategies to steer active blood vessel growth. Furthermore, we found that endothelial cells use their metabolism to communicate with the environment and to actively control muscle homeostasis. We identified that this metabolic angiocrine communication is required to maintain and restore muscle homeostasis, thereby putting the vasculature as a central player in muscle homeostasis.
Graphical abstract Fan et al. Cell Metabolism 2021
Graphical abstract Zhang et al. Cell Metabolism 2020