Exercise

Exercise has enormous health benefits. One of its major benefits is to improve insulin sensitivity in skeletal muscle thus providing protection against metabolic disease.  Despite many decades of research, the mechanism for this effect is not known.

In collaboration with Jørgen Wojtaszewski from the University of Copenhagen we have embarked upon an ambitious program in humans to investigate the mechanism by which exercise improves muscle insulin sensitivity. This involves the use of Copenhagen’s novel one-legged exercise model combined with muscle biopsies and accurate measures of muscle insulin sensitivity. These biopsies were analysed by Sean Humphrey’s state of the art phosphoproteomic pipeline and data was analysed by Elise Needham, an incredibly talented PhD student in our group. This has led to spectacular novel insights into muscle insulin sensitivity involving cross talk between the mTOR and AMPK signaling pathways.

We measured muscle biopsy phosphoproteomes to determine how exercise rewires insulin signalling. We found that exercise potentiates insulin signalling, as well as causing divergent and emergent phosphorylation events. A small subset of these phosphosites are shown below and the data are available to explore at www.personalisedphospho.com. The vast majority of phosphorylation sites haven’t been characterised in insulin signalling before. There are many opportunities to expand our knowledge of how insulin regulates cellular processes.

Out of the thousands of phosphosites regulated by exercise and insulin, it is difficult to determine which of these are most important to the biological outcomes of interest, such as muscle glucose uptake. We developed a method called “personalised phosphoproteomics” to tackle this problem. Personalised phosphoproteomics takes advantage of the observation that even amongst healthy subjects, there is a remarkably broad range in the biological response to exercise. We have recently discovered that this ‘uniqueness’ is also mirrored right down to the molecular level, with humans having their own phosphoproteome fingerprint that governs their response to exercise.