Histamine as a Molecular Transducer of Adaptation to Exercise

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PROJECT SUMMARY/ABSTRACT Exercise is an important strategy to promote and maintain healthy cardiovascular, musculoskeletal, and metabolic function. However, the signals and mechanisms which transduce these effects are poorly understood. NIH’s Director has highlighted this as a critical gap in knowledge by establishing the Common Fund program on “Molecular Transducers of Physical Activity in Humans” to identify novel mechanisms for exercise-induced health benefits. The long-term goal of this proposal is to examine in greater detail the factors that regulate exercise effects on health and function, with a focus on histamine released from mast cells in skeletal muscle. Exercise stimulates the release of histamine from mast cells in skeletal muscle, which binds to histamine receptors and may play a role in stimulating positive adaptations. Supporting evidence is that blocking histamine receptors during exercise influences more than 25% of exercise-responsive genes in skeletal muscle. The histamine footprint on the exercise transcriptome crosses many cellular functions, including vascular function, metabolism, cellular maintenance, and inflammation. However, it is not known what triggers release of histamine from skeletal muscle during exercise, how the histamine-mediated responses impact on health and function, or whether activation of histamine receptors is a necessary step on the path to the positive adaptations to aerobic exercise training. These unknowns will be addressed in the following aims: 1) Identify the exercise-related signals that cause release of histamine in skeletal muscle, and 2) Determine the broader role of histamine in longer-term adaptations to exercise training. These aims are supported by our prior work and will be addressed using state-of-the-art methods in humans. Information from these studies will prove valuable on three fronts. First, these studies will identify a key pathway that contributes to the health benefits of lifetime physical activity by modulating critical signals for adaptation, filling a critical gap in knowledge. Second, these studies will identify mechanisms (the signals for histamine release) that can be exploited by future interventions, to mimic or enhance some of the beneficial effects of exercise. This may set the stage for translational research with public health impact. Last, these studies may prove that histamine, generally associated with pathophysiological responses, is an important molecular transducer of exercise responses impacting cardiovascular, musculoskeletal, and metabolic health, enhancing our broad understanding of the human condition. In summary, these studies will add to the understanding of histamine and its receptors in treatment and prevention of disease associated with physical inactivity and set the stage for new interventions targeting at-risk populations.