Tregs promote benefitial effects of exercise by reining in interferon-mediated damage to muscle mitochondria

Exercise is a salubrious activity: it enhances physical performance and reduces the risk of modern afflictions such as cardiovascular disease, type 2 diabetes, and cancer. Exercise characteristically incites an inflammatory response, notably in skeletal muscles. While some key innate and adaptive effector immunocytes have been identified, counteracting regulatory elements remain obscure. We have addressed the roles of Foxp3+CD4+ regulatory T cells (Tregs) in the healthful activities of exercise via immunologic, transcriptomic, histologic, metabolic, and biochemical analyses of acute and chronic exercise models. Exercise rapidly induced expansion of the muscle Treg compartment, thereby guarding against over-exuberant production of interferons and consequent metabolic disruptions, particularly mitochondrial aberrancies. Importantly, typical performance enhancements resulting from exercise training were dampened in the absence of Tregs. Thus, exercise is a natural Treg booster with therapeutic potential in disease and aging contexts. To study the importance of immunomodulation, in particular Treg functions, to muscle transcriptional responses to exercise, mice were acutely exercised (Exer) or exercise-trained (EXT), and tibialis anterior (TA) and/or quadriceps (Qd) muscles were dissected and homogenized in TRIzol for RNA isolation, library construction, and whole-tissue RNA-seq. Exercised muscles were compared to muscles of sedentary (SED) controls. For loss-of-function experiments, Foxp3-expressing cells (i.e. Tregs) were punctually or continuously depleted via diphtheria toxin (DT)-mediated ablation of in Foxp3-IRES-GFP.hDTR (Foxp3DTR+). To uncover the importance of excessive IFN-gamma to impaired muscle properties in contexts of Treg-deficiency and aging, Foxp3DTR+ or 24-month-old mice were injected every other day with neutralizing anti-IFN-gamma (aIFNg) antibody or IgG for one week during EXT or rest.