Immunological bases of the beneficial effects of exercise on skeletal muscle aging

Yale University, New Haven CT

Investigators

Abstract

PROJECT SUMMARY An increase in human life expectancy without a proportional extension of time spent in good health, or “healthspan,” has led to expansion of the global population of aged and frail individuals with multiple morbidities. Chronic exercise improves healthspan in multiple model organisms, and physical activity level is inversely associated with all-cause mortality risk in humans. There is a preponderance of evidence for the benefits of physical activity and exercise in youth and during aging, yet the cellular and molecular mechanisms underpinning these benefits remain ill-defined. Previously, I demonstrated that appropriate inflammatory tone in muscles is required for normal tissue- and organism-level metabolic adaptations and improved performance in response to exercise. The current research plan will advance our understanding of exercise-induced immunomodulation and its effects on muscle physiology and age-related muscular decline. My preliminary data show that muscle stromal cells potentiate exercise-induced muscle inflammation in response to mechanical stress; this is exacerbated in aged muscles. In Aim 1, I will test the hypothesis that an appropriate level of mechanical-stress-mediated stromal activation is critical for the immunological, metabolic, and functional adaptations to exercise observed in young mice; in aged mice, excessive mechanical stress augments muscle inflammation, which limits these adaptations. In Aim 2, I will determine the contributions of muscle stromal cells and macrophages to the opposing effects of inflammation, in particular IFN, and exercise training on age-related decline in muscle function. I postulate that aging skews muscle stromal-cell and macrophage phenotypes toward states that contribute to muscular decline and that training is sufficient to counter these changes. Furthermore, I hypothesize that increased IFN signaling into stromal cells and macrophages is a basis of age-related decline in muscle function. In addition to conceptual advancements, the present proposal will generate rich transcriptomics datasets and multiple mouse strains of utility in my future independent studies. I have completed most of the Aim 1 experiments involving young mice and will continue Aim 1 in both the approval and award phases. The approval phase will be completed at Harvard Medical School in the joint-lab of Drs. Diane Mathis and Christophe Benoist, leaders in immunological tolerance and systems immunology. In the approval phase, I will work with my advisory committee to polish my skills in mentorship, grant writing, communication, and lab management. This training will be complemented with formal instruction in the form of courses and workshops designed to promote professional development and independence. I have an unwavering passion for immunometabolism, and I have structured my scientific training to afford me with a diverse skillset suitable for establishing a productive niche in which I can lead a successful laboratory. The datasets generated by this plan, in particular the transcriptomic and metabolic profiles of muscle- resident cells from the proposed experimental conditions, will inform my laboratory’s future work aimed toward understanding metabolic regulation of skeletal muscle inflammation and adaptation during exercise and aging.