Final Report Summary - AMPKANTIINFLAMMATION (Regulation of obesity and fatty acid-induced inflammation by AMP-activated protein kinase in obese/type 2 diabetic and inactive human skeletal muscle.)
Obesity is a major public health problem due to its significant association with low quality of life and increased morbidity and mortality. The increased incidence of obesity has been attributed to the “modern lifestyle”, where calorific intake of saturated fatty acids is high and physical activity low. It is now known that obesity is associated with chronic inflammation in tissues such as skeletal muscle and it is thought that this contributes to the development of obesity-associated health complications including diabetes. Skeletal muscle is central in the uptake and storage of glucose from blood following a meal, and is therefore the main target in insulin resistance (or pre-diabetes). Interestingly, human skeletal muscle contains stem cells, known as satellite cells; that are important in maintaining muscle function. In this study we have found that these human muscle stem cells, which can be grown to form muscle like tubes (Fig 1), are adversely affected by lifestyle factors such as saturated fats, physical inactivity and obesity. Importantly, these cells retain these changes (phenotypes) when they are taken out of the human and grown in the lab, allowing us to use these cells as a model of human lifestyle diseases, to increase our knowledge of the effects of lifestyle on muscle and manipulate the cells to identify potential treatments.
The overall aim of this project was to understand how lifestyle choices impact on human metabolism of satellite cells in terms of inflammatory complications of metabolic/lifestyle diseases such as obesity and diabetes.
The main findings of this research were:
• Human satellite cells that are grown in the lab have a “memory” of what they were inside the body i.e. they exhibit metabolic differences that are associated with physical activity level, diet and diabetes.
• Satellite cells from obese-type 2 diabetic people are significantly inflamed when compared to cells from lean and obese-non-diabetic controls.
• Pharmacological activation of AMP-activated protein kinase (AMPK), which can also be activated in muscle by exercise, reduces inflammation in satellite cells taken from obese-type 2 diabetic people.
• An inactive sedentary lifestyle impacts on human satellite cells making them insulin resistant (pre-diabetic) when given saturated fat but does not cause inflammation.
• Exercise throughout life partially prevents the development of fat-induced insulin resistance in human satellite cells.
• Short periods of inactivity (2 weeks) in combination with a high fat diet is sufficient to reduce insulin response in human satellite cells but does not cause inflammation.
In conclusion, we now know that lifestyle choices or diseases such as obesity effect the metabolism of human muscle stem cells and we have provided strong evidence that these cells can be used for investigating metabolic diseases (including diabetes and obesity) and adaptations to exercise. Satellite cells are therefore a useful tool to understand multiple diseases in human cells rather than in animals.
Although we know that exercise is good for you and that a bad diet has severe consequences for the body, this study shows that these lifestyle factors have significant effects on the metabolism of human muscle stem cells. Satellite cells are thought to have important roles in muscle repair and function and therefore, changes in their metabolism could significantly impact on muscle and subsequently whole body health in general. The finding that AMPK is such a robust anti-inflammatory protein suggests that a new area of drug research could come from this to investigate potential AMPK-activating drugs to treat inflammatory diseases. It is important to note that the anti-diabetic drug metformin, that is widely prescribed, is also an activator of AMPK. Therefore it may be useful as an already FDA approved drug in humans, to treat some of the inflammatory complications that arise in obesity. This research also provides evidence that exercise is a natural and powerful way to prevent or delay the development of insulin resistance in satellite cells and potentially inflammation in muscle through AMPK activation. These findings could be relevant to a wide range of groups including: clinical trial researchers, general practitioners, government and the general public. There is currently emphasis on the value of healthy lifestyle, with multiple programmes and news segments both on obesity and the true value of exercise, and this research will help to educate and raise awareness of the effects of lifestyle on your body.