Exercise is essential in regulating energy metabolism and remains the most promising therapy for obesity and type 2 diabetes. However, the intricate cellular signalling networks underlying tissue responses to exercise-stimulated metabolic and mechanical stress are not fully understood. Global, unbiased discovery approaches are warranted to map these complex, interconnected molecular networks that promote the systemic health benefits of exercise.
Protein phosphorylation is central to a range of exercise-induced tissue adaptations including regulation of skeletal muscle metabolism and contraction. Therefore, we previously undertook a global mass spectrometry-based phosphoproteomic analysis comparing human skeletal muscle biopsies before and after a high-intensity exercise bout (1). This revealed over 1,000 exercise-regulated phosphorylation sites on over 500 proteins, including a majority of kinases and phosphosites never previously implicated in exercise signalling. Furthermore, novel exercise-regulated substrates of the energy-sensing AMP-activated protein kinase (AMPK) were uncovered using this global approach. Ongoing studies will be discussed that are aimed at determining how components of the acute exercise signalling network are impacted by skeletal muscle contraction and nutrient availability.
Collectively, multidisciplinary global phosphoproteomics and targeted physiological approaches have led to the discovery of exercise biological targets and new roles for kinases such as AMPK. This rapidly expanding frontier in understanding the molecular underpinnings of exercise will aid development of therapeutic strategies to improve human health and target obesity-related pathophysiology.