Interleukin-13 drives metabolic conditioning of muscle to endurance exercise

Abstract

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.

Differential effects on blood and cerebrospinal fluid immune protein markers and kynurenine pathway metabolites from aerobic physical exercise in healthy subjects

“…Based on findings in prior studies, a number of cytokines were expected to occur in measurable levels and increase in response to the interventions. These include IL-6, a central myokine associated with muscle growth and regulation of energy metabolism, the newly discovered IL-13, necessary for development of muscle endurance with exercise, brain-derived neurotrophic factor (BDNF), which has been observed to increase in blood proportionally to exercise intensity, and interferon (IFN)-γ/α, necessary for induction of indoleamine 2,3-dioxygenase (IDO) as part of the KP 30 , 33 – 35 . It is likely that the inability to reliably detect these proteins here depend on technical issues, such as for example the performance of the antibodies used for detection and that other assay platforms might display improved sensitivity for these particular targets.…”

Molecular Basis for the Therapeutic Effects of Exercise on Mitochondrial Defects

“…Moreover, the regulatory regions of nuclear genes encoding mitochondrial proteins are heterogeneous and therefore, the regulation of organelle synthesis requires multiple regulators of transcription ( Lenka et al, 1998 ; Hood, 2001 ). A number of transcription factors associated with exercise-induced mitochondrial biogenesis have been established, such as CREB, the estrogen related receptors (ERRα,β, γ ), c-myc, specificity protein-1 (Sp-1), upstream stimulatory factor-1 (USF-1), as well as nuclear respiratory factors 1 and 2 (NRF1 and NRF2) (see Islam et al, 2020 for review; Hood et al, 2011 ; Knudsen et al, 2020 ). Each transcription factor when bound to target gene promoter sequences can upregulate the expression of mitochondrial proteins.…”

Exercise and Adipose Tissue Immunity: Outrunning Inflammation

“…Emerging evidence links effector functions of various tissue resident immune cells with the metabolic demands of both acute exercise and long‐term exercise adaptations (e.g., mitochondrial biogenesis, mitochondrial density, and oxidative capacity). A recent study (94) suggests that type 2 innate lymphoid cell–derived IL‐13 is critical for endurance capacity and oxidative metabolism in mouse skeletal muscle. Using multiple whole‐body and skeletal muscle–specific genetic approaches, results suggest that IL‐13 mediates its effects via IL‐13Rα signaling, leading to phosphorylation of Stat3 (p‐Stat) and engagement of the orphan receptors Estrogen‐related receptor alpha and Estrogen‐related receptor gamma in skeletal muscle cells.…”

“…Moreover, bilateral adenoviral IL‐13 injection (gain of function) into the gastrocnemius muscle increased exercise time to exhaustion, glucose tolerance, and fatty acid oxidation in the gastrocnemius and increased p‐Stat3 in quadriceps muscle. Thus, studies in these genetic models suggest that IL‐13–mediated signaling in myofibers is indeed important for endurance capacity and nutrient use (94), likely through glycogen sparing effects. Although these studies were focused on skeletal muscle, it begs the question of whether similar cooperation exists among immune and parenchymal cells during exercise in AT.…”