Interleukin-13 drives metabolic conditioning of muscle to endurance exercise

IL-13 hits the gym Interleukin-13 (IL-13) is a cytokine secreted by T cells, innate lymphoid cells (ILC2s), and granulocytes. It acts as a central mediator in allergy and antihelminth defense with various effects. Knudsen et al. report a distinct role for IL-13 in exercise and metabolism (see the Perspective by Correia and Ruas). Mice subjected to endurance training showed increases in circulating IL-13, which correlated with ILC2 expansion in the muscles. By contrast, exercise-induced increases in muscle fatty acid utilization and mitochondrial biogenesis were erased when mice lacked IL-13. Activation of signaling pathways downstream of the muscle IL-13 receptor was key to this effect. Intramuscular injection of adenoviral IL-13 could recapitulate exercise-induced metabolic reprogramming. This signaling pathway may have evolved to combat the metabolic stresses of parasite infection. Science, this issue p. eaat3987; see also p. 470 Interleukin-13 enhances muscle fuel economy after endurance exercise. INTRODUCTION Exercise provides a vast array of health benefits. The increased metabolic activity of contracting skeletal muscle elicits an integrated response involving multiple tissues and signaling pathways to cope with increased energy and oxygen demands. A coordinated effort to promote endurance is mediated by a switch from glycolytic to oxidative metabolism favoring fatty acids as the energy source. This metabolic fueling strategy is met with specialized muscle fibers that exhibit distinct energy substrate preferences and mitochondrial oxidative capacity. These adaptive changes—such as increased cardiorespiratory capacity, enhanced muscle oxidative metabolism, and improved whole-body glucose homeostasis—promote metabolic fitness. However, the mechanisms that mediate these adaptive responses remain unclear. RATIONALE In the early 1960s, labile blood and lymph factors were found to mediate some of the metabolic effects of exercise. Recent studies further support the notion that communication between resident immune cells and their host tissues is important for regulating the metabolic setpoint and thereby maintaining tissue function. We found that endurance exercise increased circulating levels of the cytokine interleukin-13 (IL-13) in mice and humans. Endurance exercise also led to the expansion of type 2 innate lymphoid cells (ILC2s), one of the primary IL-13–producing cell types within mouse muscle. This implicated a role for IL-13 in the control of the adaptive responses elicited by exercise. We used several molecular and bioenergetic assays and generated three genetic models to determine the role of IL-13 signaling in the metabolic reprogramming of skeletal muscle in response to endurance exercise training. RESULTS Relative to wild-type control animals, Il13-deficient mice showed reduced running capacity on a treadmill. RNA sequencing of skeletal muscle from control and Il13-deficient mice was performed to examine the role of IL-13 in exercise physiology. IL-13 did not have an appreciable effect on metabolic gene expression in resting muscles. However, endurance training increased a network of mitochondrial and fatty acid oxidation genes in muscle of control animals, which was lost in mice lacking Il13. Il13-deficient muscle showed defective fatty acid utilization after a single bout of exercise and failed to increase mitochondrial biogenesis after endurance training. Furthermore, endurance training in control animals led to increased numbers of muscle oxidative fibers and improvements in mitochondrial respiration, endurance capacity, and glucose tolerance. All of these metabolic benefits of exercise training required intact IL-13 signaling. We found that IL-13 acts directly on skeletal muscle through its receptor IL-13Rα1, leading to the activation of Stat3. Stat3 phosphorylation was elevated in muscle after both a single session and endurance training—an effect lost in Il13-deficient mice. In C2C12 myotubes, IL-13 treatment increased mitochondrial respiration that was dependent on Il13ra1 and Stat3. The IL-13–Stat3 axis controlled the metabolic program elicited by exercise training partly through a coordinated transcriptional regulation with two nuclear receptors and mitochondrial regulators, ERRα and ERRγ. Mice specifically lacking Il13ra1 or Stat3 in skeletal muscle displayed reductions in muscle fatty acid oxidation and endurance capacity. By contrast, increasing levels of IL-13 in skeletal muscle recapitulated the metabolic reprogramming induced by endurance exercise in a Stat3-dependent manner, leading to improvements in systemic glucose homeostasis and running capacity. CONCLUSION IL-13 signaling appears to be activated immediately after exercise and stabilized by endurance training, with the effects of modulating substrate utilization and mediating mitochondrial biogenesis, respectively. As such, it fits the criteria of a humoral factor that regulates exercise-induced metabolic effects. IL-13 exerts direct effects on skeletal muscle to increase transcriptional programs encoding fatty acid oxidation and mitochondrial electron transport chain complexes through IL-13Rα1 and the downstream effector Stat3. This adaptive response, an interplay of the immune and metabolic pathways, primes muscle for sustained physical activity. These observations highlight the importance of immune signaling in the maintenance of tissue metabolic fitness. IL-13 mediates muscle metabolic programming to support endurance exercise via IL-13Rα1 and Stat3. Image shows gastrocnemius muscle cross section stained for myosin heavy chain (MyHC) isoforms to determine muscle fiber type composition. Blue, green, and red indicate MyHC I-, IIa-, and IIb-positive muscle fibers, respectively. Type I and type IIa muscles contain more oxidative fibers and are characterized by high endurance, whereas type IIb muscle fibers are glycolytic and prone to fatigue. Repeated bouts of exercise condition muscle mitochondria to meet increased energy demand—an adaptive response associated with improved metabolic fitness. We found that the type 2 cytokine interleukin-13 (IL-13) is induced in exercising muscle, where it orchestrates metabolic reprogramming that preserves glycogen in favor of fatty acid oxidation and mitochondrial respiration. Exercise training–mediated mitochondrial biogenesis, running endurance, and beneficial glycemic effects were lost in Il13–/– mice. By contrast, enhanced muscle IL-13 signaling was sufficient to increase running distance, glucose tolerance, and mitochondrial activity similar to the effects of exercise training. In muscle, IL-13 acts through both its receptor IL-13Rα1 and the transcription factor Stat3. The genetic ablation of either of these downstream effectors reduced running capacity in mice. Thus, coordinated immunological and physiological responses mediate exercise-elicited metabolic adaptations that maximize muscle fuel economy.