Molecular mechanisms of metabolic adaptation to endurance exercise

Abstract

Adaptation of cellular metabolism allows tissues to perform diverse, specialized functions. Endurance exercise training promotes aerobic oxidation of metabolic substrates in skeletal muscle by increasing mitochondrial capacity to utilize fatty acids supplied by lipolysis in white adipose tissue and spare stored glycogen. This metabolic fueling strategy sustains energy production during long bouts of exercise. In my thesis, I will outline how a cytokine produced locally by immune cells drives the conditioning of muscle and white adipose tissue to endurance exercise. The first study establishes that the metabolic adaptation of skeletal muscle to endurance exercise training is governed by the cytokine interleukin-13 (Il-13), which also mediates the metabolic benefits of endurance exercise training, including increasing muscle mitochondrial function and glucose tolerance. Il-13 activates signal transducer and activator of transcription 3 (Stat3) to increase transcription of a network of genes involved in fatty acid uptake and oxidation, mitochondrial respiration, and glycogen synthesis. In the second study, I demonstrate that in addition to its function in skeletal muscle, Il-13 acts as a critical regulator of beige adipose tissue development in response to β-adrenergic signaling. Lastly, I discuss two non-transcriptional mechanisms of Il-13 signaling that enhance mitochondrial oxidative metabolism in skeletal muscle. Collectively, my work highlights the complex role of immune signaling in integrating tissue metabolism with the physiological demands of endurance exercise.