Exerkines in health, resilience and disease
Comprehensive Overview
Published in Nature Reviews Endocrinology in 2022, this review article asks how exercise produces its wide-ranging health benefits, from a healthier heart to better mood and blood sugar control, given that the specific molecular messengers responsible have remained poorly understood despite decades of research. The authors focus on "exerkines," a general term for signaling molecules, including hormones, proteins, and genetic material, that muscles and other organs release into the bloodstream during or after exercise to communicate with distant tissues. This synthesis grew out of a 2020 workshop sponsored by two National Institutes of Health institutes, where 21 international exercise researchers reviewed accumulated evidence on how these molecules are produced by tissues such as skeletal muscle, the heart, liver, fat, and brain, and how they act locally or travel through the blood to influence organs elsewhere in the body. The topline conclusion was that this field, which began with the 2000 discovery that contracting muscle releases the messenger interleukin-6, has expanded rapidly to include dozens of candidate exerkines with potential roles in preventing and treating cardiovascular disease, diabetes, obesity, and cognitive decline, though most of the underlying mechanisms remain incompletely defined.
Outcomes and Implications
The single most important takeaway was that exerkines operate as a genuinely multi-organ signaling network rather than a narrow set of muscle-derived factors, with the heart, liver, white and brown fat, gut, and nervous system all producing and responding to these molecules to coordinate the body's adaptation to exercise. Some exerkines act locally on the cells that release them, while others travel through the bloodstream to distant organs; well-studied examples include interleukin-6, the original myokine, which helps regulate fat metabolism and inflammation, and brain-derived neurotrophic factor, which rises with acute exercise and appears to support memory and mood by promoting neuron growth in the brain's hippocampus. The authors also highlighted important nuance and unresolved controversy, noting that the immediate exerkine response to a single exercise session does not always predict the long-term effects of regular training, that findings in mice frequently fail to replicate in humans, such as with the fat-browning hormone irisin, and that inconsistent study methods have made results difficult to compare across research groups. Because exercise is not equally accessible to everyone, including people with physical limitations, chronic illness, or restricted mobility, the authors argue that fully characterizing exerkines could eventually allow some of exercise's benefits to be delivered through targeted treatments or an "exercise pill" for those unable to exercise themselves, and they call for large, standardized studies, such as the ongoing NIH-funded MoTrPAC consortium, alongside wearable technology to better capture how these molecules drive healthy aging and disease prevention.