Paediatric metabolic dysfunction-associated steatotic liver disease (MASLD) has become the most common chronic liver disease in children and can lead to liver fibrosis, cirrhosis and hepatocellular carcinoma. No pharmacological treatment is available, except in clinical trials, which are performed almost exclusively in adults. While there is growing evidence that obesity-related metabolic diseases are associated with muscle dysfunction, and while multimodal lifestyle management is the preferred treatment for paediatric obesity, the interaction between liver, muscle and exercise in MASLD is incompletely understood, especially in children.
Building on the ‘developmental origins of health and disease’ hypothesis, increasing evidence indicates that the intrauterine and early life environment have long-term metabolic effects. A recent systematic review by our group confirmed that maternal obesity promotes offspring MASLD. However, the transgenerational impact of exercise on the liver is still unclear.
In this project, we will chart the muscle-liver axis by investigating the therapeutic efficacy of maternal and early-life exercise in a novel murine model of paediatric MASLD (promising data underline the feasibility and validity). Next, we will analyse serum levels of muscle-secreted factors, myokines, in a unique and large (350+ recruited so far) paediatric obesity cohort, and correlate these to MASLD severity to identify potential biomarkers. Finally, the relation between MASLD and skeletal muscle mitochondrial dysfunction will be investigated in both patients and our animal model, allowing us to unravel the molecular mechanisms that underlie the muscle-liver axis in paediatric MASLD – and thereby identify new treatment targets.