The Link Between Metabolism and Fibrosis in People With Scleroderma

A new study from the UK has identified a possible connection between metabolism and fibrosis in people with scleroderma, with the potential to open up new treatment avenues in the future.

Metabolism refers to the ways in which our cells release energy from the foods we eat. There are several forms that this process can take, and researchers have recently identified that certain metabolic reactions could play a role in driving inflammation within the cells of the body. This could contribute to the production of excess collagen, eventually leading to fibrosis. These findings could represent a significant development in the management of scleroderma; with the potential for new treatments to be made available in the future.

The human body is the ultimate machine, capable of carrying out a range of complex tasks each day. Underpinning this is our ‘metabolism’. Like a car burns petrol, the cells in our bodies use the oxygen we breathe to ‘burn’ glucose, providing the energy needed to sustain life.

Energy release from glucose occurs through a series of chemical reactions. Some of these are ‘aerobic’ reactions, which involve oxygen. Aerobic reactions release energy from glucose via the most efficient pathway; therefore this is usually how our cells generate the energy we need to carry out our daily activities.

Sometimes, large amounts of energy are needed quickly, and our cells may not be able to get enough oxygen from the bloodstream to satisfy these demands. In these oxygen-limiting conditions our body cells rely on ‘anaerobic reactions’, that quickly release small amounts of energy without using oxygen. This method produces a by-product called lactate. You can often feel lactate when you exercise; it is what makes your muscles ache. If you hold your arms out to the side, an ache will build up as lactate is produced. When you lower your arms again, this will subside as the lactate is broken down.

The ‘medical’ importance of ‘metabolism’ was discovered in the 1920s when scientist Otto Warburg observed that even in oxygen-abundant conditions, cancer cells rely on the series of reactions which generate lactate along with other by-products to produce energy. This was termed the ‘Warburg effect’. In recent years, the importance of the Warburg effect has been demonstrated in autoimmune conditions where it is believed to drive inflammation in immune cells.  New research led by scientists based at Durham University and University College London points towards the contribution of altered cellular metabolism to fibrosis.

The research showed that a mild version of the Warburg effect takes place in tissue samples affected by fibrosis from scleroderma patients, and that energy is also generated through a second pathway known as ‘glutamine metabolism’. These reactions generate by-products which stimulate fibrosis and contribute to the production of collagen, which causes fibrosis. The researchers suggest that this altered pathway could be partly responsible for the fibrosis observed in scleroderma - more visibly seen as skin thickening.

Eventually these findings could result in the development of new treatments for scleroderma which target the metabolic pathways that underly fibrosis. The researchers suggest it may be possible to repurpose existing drugs, for example those which target similar mechanisms in cancer cells. The group have carried out some initial work in this area, treating the patient tissue samples with an anti-inflammatory molecule called 4-octyl itaconate. This anti-inflammatory molecule was shown in the laboratory to reduce collagen levels in the cells which cause fibrosis from some patients with scleroderma.

Hopefully these exciting discoveries could lead to new drugs treating fibrosis within scleroderma, which could significantly improve quality of life for those living with the condition.  

Metabolic reprogramming of glycolysis and glutamine metabolism are key events in myofibroblast transition in systemic sclerosis pathogenesis - Henderson - 2020 - Journal of Cellular and Molecular Medicine - Wiley Online Library